Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial
Identifieur interne : 004416 ( Pmc/Corpus ); précédent : 004415; suivant : 004417Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial
Auteurs : Tae Ho Kim ; Jae Seung Chang ; Kyu-Sang Park ; Jeeyeon Park ; Nahyun Kim ; Jong In Lee ; In Deok KongSource :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
Wingless and integration site growth factor (Wnt) signaling is a tumorigenesis-related signaling pathway. Dickkpof-1 (DKK1) and secreted frizzled-related protein-1 (SFRP1) are endogenous negative regulators of Wnt/β-catenin signaling. Accumulating evidence indicates that higher serum levels of DKK1 are correlated with poor prognosis of various types of cancer. Here, we investigated whether exercise training causes changes in the serum levels of DKK1 and SFRP1 in patients with breast cancer.
Twenty-four breast cancer survivors, after chemo- or radiotherapy, participated in this single-blind randomized, controlled pilot study. Subjects were randomized to either an exercise program or a control group for 12 weeks and completed pre- and post-training tests for health-related fitness and body composition as well as blood biomarkers. The serum levels of DKK1 and SFRP1 were measured using enzyme-linked immunosorbent assay as the primary outcome.
Exercise training for 12 weeks remarkably increased muscle strength, endurance, and flexibility and decreased body fat percentage, waist circumference, and visceral fat area (all
Our results indicate that DKK1 and SFRP1 may be potentially useful biomarkers for evaluating the beneficial effects of long-term exercise on physical fitness and metabolism as well as the prognosis of patients with cancer.
ClinicalTrials.gov
Url:
DOI: 10.1371/journal.pone.0171771
PubMed: 28178355
PubMed Central: 5298304
Links to Exploration step
PMC:5298304Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial</title><author><name sortKey="Kim, Tae Ho" sort="Kim, Tae Ho" uniqKey="Kim T" first="Tae Ho" last="Kim">Tae Ho Kim</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang, Jae Seung" sort="Chang, Jae Seung" uniqKey="Chang J" first="Jae Seung" last="Chang">Jae Seung Chang</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Kyu Sang" sort="Park, Kyu Sang" uniqKey="Park K" first="Kyu-Sang" last="Park">Kyu-Sang Park</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Jeeyeon" sort="Park, Jeeyeon" uniqKey="Park J" first="Jeeyeon" last="Park">Jeeyeon Park</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Nursing Science, Kyungsung University, Busan, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kim, Nahyun" sort="Kim, Nahyun" uniqKey="Kim N" first="Nahyun" last="Kim">Nahyun Kim</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Basic Nursing Science, Keimyung University College of Nursing, Daegu, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lee, Jong In" sort="Lee, Jong In" uniqKey="Lee J" first="Jong In" last="Lee">Jong In Lee</name><affiliation><nlm:aff id="aff005"><addr-line>Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kong, In Deok" sort="Kong, In Deok" uniqKey="Kong I" first="In Deok" last="Kong">In Deok Kong</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28178355</idno><idno type="pmc">5298304</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298304</idno><idno type="RBID">PMC:5298304</idno><idno type="doi">10.1371/journal.pone.0171771</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">004416</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004416</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial</title><author><name sortKey="Kim, Tae Ho" sort="Kim, Tae Ho" uniqKey="Kim T" first="Tae Ho" last="Kim">Tae Ho Kim</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang, Jae Seung" sort="Chang, Jae Seung" uniqKey="Chang J" first="Jae Seung" last="Chang">Jae Seung Chang</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Kyu Sang" sort="Park, Kyu Sang" uniqKey="Park K" first="Kyu-Sang" last="Park">Kyu-Sang Park</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Jeeyeon" sort="Park, Jeeyeon" uniqKey="Park J" first="Jeeyeon" last="Park">Jeeyeon Park</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Nursing Science, Kyungsung University, Busan, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kim, Nahyun" sort="Kim, Nahyun" uniqKey="Kim N" first="Nahyun" last="Kim">Nahyun Kim</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Basic Nursing Science, Keimyung University College of Nursing, Daegu, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lee, Jong In" sort="Lee, Jong In" uniqKey="Lee J" first="Jong In" last="Lee">Jong In Lee</name><affiliation><nlm:aff id="aff005"><addr-line>Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kong, In Deok" sort="Kong, In Deok" uniqKey="Kong I" first="In Deok" last="Kong">In Deok Kong</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Wingless and integration site growth factor (Wnt) signaling is a tumorigenesis-related signaling pathway. Dickkpof-1 (DKK1) and secreted frizzled-related protein-1 (SFRP1) are endogenous negative regulators of Wnt/β-catenin signaling. Accumulating evidence indicates that higher serum levels of DKK1 are correlated with poor prognosis of various types of cancer. Here, we investigated whether exercise training causes changes in the serum levels of DKK1 and SFRP1 in patients with breast cancer.</p></sec><sec id="sec002"><title>Methods</title><p>Twenty-four breast cancer survivors, after chemo- or radiotherapy, participated in this single-blind randomized, controlled pilot study. Subjects were randomized to either an exercise program or a control group for 12 weeks and completed pre- and post-training tests for health-related fitness and body composition as well as blood biomarkers. The serum levels of DKK1 and SFRP1 were measured using enzyme-linked immunosorbent assay as the primary outcome.</p></sec><sec id="sec003"><title>Results</title><p>Exercise training for 12 weeks remarkably increased muscle strength, endurance, and flexibility and decreased body fat percentage, waist circumference, and visceral fat area (all <italic>p</italic> < 0.05). Exercise training lowered serum insulin levels and leptin/adiponectin ratios (all <italic>p</italic> < 0.05). The levels of DKK1 and SFRP1 were also significantly decreased by exercise training in breast cancer survivors (all <italic>p</italic> < 0.01).</p></sec><sec id="sec004"><title>Conclusions</title><p>Our results indicate that DKK1 and SFRP1 may be potentially useful biomarkers for evaluating the beneficial effects of long-term exercise on physical fitness and metabolism as well as the prognosis of patients with cancer.</p></sec><sec id="sec005"><title>Trial registration</title><p>ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02895178">NCT02895178</ext-link></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Binkley, Jm" uniqKey="Binkley J">JM Binkley</name></author><author><name sortKey="Harris, Sr" uniqKey="Harris S">SR Harris</name></author><author><name sortKey="Levangie, Pk" uniqKey="Levangie P">PK Levangie</name></author><author><name sortKey="Pearl, M" uniqKey="Pearl M">M Pearl</name></author><author><name sortKey="Guglielmino, J" uniqKey="Guglielmino J">J Guglielmino</name></author><author><name sortKey="Kraus, V" uniqKey="Kraus V">V Kraus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loprinzi, Pd" uniqKey="Loprinzi P">PD Loprinzi</name></author><author><name sortKey="Cardinal, Bj" uniqKey="Cardinal B">BJ Cardinal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Knols, R" uniqKey="Knols R">R Knols</name></author><author><name sortKey="Aaronson, Nk" uniqKey="Aaronson N">NK Aaronson</name></author><author><name sortKey="Uebelhart, D" uniqKey="Uebelhart D">D Uebelhart</name></author><author><name sortKey="Fransen, J" uniqKey="Fransen J">J Fransen</name></author><author><name sortKey="Aufdemkampe, G" uniqKey="Aufdemkampe G">G Aufdemkampe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcneely, Ml" uniqKey="Mcneely M">ML McNeely</name></author><author><name sortKey="Campbell, Kl" uniqKey="Campbell K">KL Campbell</name></author><author><name sortKey="Rowe, Bh" uniqKey="Rowe B">BH Rowe</name></author><author><name sortKey="Klassen, Tp" uniqKey="Klassen T">TP Klassen</name></author><author><name sortKey="Mackey, Jr" uniqKey="Mackey J">JR Mackey</name></author><author><name sortKey="Courneya, Ks" uniqKey="Courneya K">KS Courneya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Polakis, P" uniqKey="Polakis P">P Polakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anastas, Jn" uniqKey="Anastas J">JN Anastas</name></author><author><name sortKey="Moon, Rt" uniqKey="Moon R">RT Moon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brennan, Kr" uniqKey="Brennan K">KR Brennan</name></author><author><name sortKey="Brown, Am" uniqKey="Brown A">AM Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schlange, T" uniqKey="Schlange T">T Schlange</name></author><author><name sortKey="Matsuda, Y" uniqKey="Matsuda Y">Y Matsuda</name></author><author><name sortKey="Lienhard, S" uniqKey="Lienhard S">S Lienhard</name></author><author><name sortKey="Huber, A" uniqKey="Huber A">A Huber</name></author><author><name sortKey="Hynes, Ne" uniqKey="Hynes N">NE Hynes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Surana, R" uniqKey="Surana R">R Surana</name></author><author><name sortKey="Sikka, S" uniqKey="Sikka S">S Sikka</name></author><author><name sortKey="Cai, W" uniqKey="Cai W">W Cai</name></author><author><name sortKey="Shin, Em" uniqKey="Shin E">EM Shin</name></author><author><name sortKey="Warrier, Sr" uniqKey="Warrier S">SR Warrier</name></author><author><name sortKey="Tan, Hj" uniqKey="Tan H">HJ Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baron, R" uniqKey="Baron R">R Baron</name></author><author><name sortKey="Kneissel, M" uniqKey="Kneissel M">M Kneissel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gough, Nr" uniqKey="Gough N">NR Gough</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Niehrs, C" uniqKey="Niehrs C">C Niehrs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Niehrs, C" uniqKey="Niehrs C">C Niehrs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheldahl, Lc" uniqKey="Sheldahl L">LC Sheldahl</name></author><author><name sortKey="Park, M" uniqKey="Park M">M Park</name></author><author><name sortKey="Malbon, Cc" uniqKey="Malbon C">CC Malbon</name></author><author><name sortKey="Moon, Rt" uniqKey="Moon R">RT Moon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuhl, M" uniqKey="Kuhl M">M Kuhl</name></author><author><name sortKey="Sheldahl, Lc" uniqKey="Sheldahl L">LC Sheldahl</name></author><author><name sortKey="Malbon, Cc" uniqKey="Malbon C">CC Malbon</name></author><author><name sortKey="Moon, Rt" uniqKey="Moon R">RT Moon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, Sj" uniqKey="Zhou S">SJ Zhou</name></author><author><name sortKey="Zhuo, Sr" uniqKey="Zhuo S">SR Zhuo</name></author><author><name sortKey="Yang, Xq" uniqKey="Yang X">XQ Yang</name></author><author><name sortKey="Qin, Cx" uniqKey="Qin C">CX Qin</name></author><author><name sortKey="Wang, Zl" uniqKey="Wang Z">ZL Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rachner, Td" uniqKey="Rachner T">TD Rachner</name></author><author><name sortKey="Gobel, A" uniqKey="Gobel A">A Gobel</name></author><author><name sortKey="Benad Mehner, P" uniqKey="Benad Mehner P">P Benad-Mehner</name></author><author><name sortKey="Hofbauer, Lc" uniqKey="Hofbauer L">LC Hofbauer</name></author><author><name sortKey="Rauner, M" uniqKey="Rauner M">M Rauner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Niida, A" uniqKey="Niida A">A Niida</name></author><author><name sortKey="Hiroko, T" uniqKey="Hiroko T">T Hiroko</name></author><author><name sortKey="Kasai, M" uniqKey="Kasai M">M Kasai</name></author><author><name sortKey="Furukawa, Y" uniqKey="Furukawa Y">Y Furukawa</name></author><author><name sortKey="Nakamura, Y" uniqKey="Nakamura Y">Y Nakamura</name></author><author><name sortKey="Suzuki, Y" uniqKey="Suzuki Y">Y Suzuki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kawano, Y" uniqKey="Kawano Y">Y Kawano</name></author><author><name sortKey="Kypta, R" uniqKey="Kypta R">R Kypta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bernemann, C" uniqKey="Bernemann C">C Bernemann</name></author><author><name sortKey="Hulsewig, C" uniqKey="Hulsewig C">C Hulsewig</name></author><author><name sortKey="Ruckert, C" uniqKey="Ruckert C">C Ruckert</name></author><author><name sortKey="Schafer, S" uniqKey="Schafer S">S Schafer</name></author><author><name sortKey="Blumel, L" uniqKey="Blumel L">L Blumel</name></author><author><name sortKey="Hempel, G" uniqKey="Hempel G">G Hempel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voorzanger Rousselot, N" uniqKey="Voorzanger Rousselot N">N Voorzanger-Rousselot</name></author><author><name sortKey="Goehrig, D" uniqKey="Goehrig D">D Goehrig</name></author><author><name sortKey="Journe, F" uniqKey="Journe F">F Journe</name></author><author><name sortKey="Doriath, V" uniqKey="Doriath V">V Doriath</name></author><author><name sortKey="Body, Jj" uniqKey="Body J">JJ Body</name></author><author><name sortKey="Clezardin, P" uniqKey="Clezardin P">P Clezardin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voorzanger Rousselot, N" uniqKey="Voorzanger Rousselot N">N Voorzanger-Rousselot</name></author><author><name sortKey="Journe, F" uniqKey="Journe F">F Journe</name></author><author><name sortKey="Doriath, V" uniqKey="Doriath V">V Doriath</name></author><author><name sortKey="Body, Jj" uniqKey="Body J">JJ Body</name></author><author><name sortKey="Garnero, P" uniqKey="Garnero P">P Garnero</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, Sx" uniqKey="Han S">SX Han</name></author><author><name sortKey="Zhou, X" uniqKey="Zhou X">X Zhou</name></author><author><name sortKey="Sui, X" uniqKey="Sui X">X Sui</name></author><author><name sortKey="He, Cc" uniqKey="He C">CC He</name></author><author><name sortKey="Cai, Mj" uniqKey="Cai M">MJ Cai</name></author><author><name sortKey="Ma, Jl" uniqKey="Ma J">JL Ma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rachner, Td" uniqKey="Rachner T">TD Rachner</name></author><author><name sortKey="Thiele, S" uniqKey="Thiele S">S Thiele</name></author><author><name sortKey="Gobel, A" uniqKey="Gobel A">A Gobel</name></author><author><name sortKey="Browne, A" uniqKey="Browne A">A Browne</name></author><author><name sortKey="Fuessel, S" uniqKey="Fuessel S">S Fuessel</name></author><author><name sortKey="Erdmann, K" uniqKey="Erdmann K">K Erdmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="D Amico, L" uniqKey="D Amico L">L D'Amico</name></author><author><name sortKey="Mahajan, S" uniqKey="Mahajan S">S Mahajan</name></author><author><name sortKey="Capietto, Ah" uniqKey="Capietto A">AH Capietto</name></author><author><name sortKey="Yang, Z" uniqKey="Yang Z">Z Yang</name></author><author><name sortKey="Zamani, A" uniqKey="Zamani A">A Zamani</name></author><author><name sortKey="Ricci, B" uniqKey="Ricci B">B Ricci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kerschan Schindl, K" uniqKey="Kerschan Schindl K">K Kerschan-Schindl</name></author><author><name sortKey="Thalmann, Mm" uniqKey="Thalmann M">MM Thalmann</name></author><author><name sortKey="Weiss, E" uniqKey="Weiss E">E Weiss</name></author><author><name sortKey="Tsironi, M" uniqKey="Tsironi M">M Tsironi</name></author><author><name sortKey="Foger Samwald, U" uniqKey="Foger Samwald U">U Foger-Samwald</name></author><author><name sortKey="Meinhart, J" uniqKey="Meinhart J">J Meinhart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bayod, S" uniqKey="Bayod S">S Bayod</name></author><author><name sortKey="Mennella, I" uniqKey="Mennella I">I Mennella</name></author><author><name sortKey="Sanchez Roige, S" uniqKey="Sanchez Roige S">S Sanchez-Roige</name></author><author><name sortKey="Lalanza, Jf" uniqKey="Lalanza J">JF Lalanza</name></author><author><name sortKey="Escorihuela, Rm" uniqKey="Escorihuela R">RM Escorihuela</name></author><author><name sortKey="Camins, A" uniqKey="Camins A">A Camins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Irwin, Ml" uniqKey="Irwin M">ML Irwin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Borg, Ga" uniqKey="Borg G">GA Borg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fairey, As" uniqKey="Fairey A">AS Fairey</name></author><author><name sortKey="Courneya, Ks" uniqKey="Courneya K">KS Courneya</name></author><author><name sortKey="Field, Cj" uniqKey="Field C">CJ Field</name></author><author><name sortKey="Bell, Gj" uniqKey="Bell G">GJ Bell</name></author><author><name sortKey="Jones, Lw" uniqKey="Jones L">LW Jones</name></author><author><name sortKey="Martin, Bs" uniqKey="Martin B">BS Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Winters Stone, Km" uniqKey="Winters Stone K">KM Winters-Stone</name></author><author><name sortKey="Dobek, J" uniqKey="Dobek J">J Dobek</name></author><author><name sortKey="Bennett, Ja" uniqKey="Bennett J">JA Bennett</name></author><author><name sortKey="Nail, Lm" uniqKey="Nail L">LM Nail</name></author><author><name sortKey="Leo, Mc" uniqKey="Leo M">MC Leo</name></author><author><name sortKey="Schwartz, A" uniqKey="Schwartz A">A Schwartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Dn" uniqKey="Chan D">DN Chan</name></author><author><name sortKey="Lui, Ly" uniqKey="Lui L">LY Lui</name></author><author><name sortKey="So, Wk" uniqKey="So W">WK So</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riesco, E" uniqKey="Riesco E">E Riesco</name></author><author><name sortKey="Choquette, S" uniqKey="Choquette S">S Choquette</name></author><author><name sortKey="Audet, M" uniqKey="Audet M">M Audet</name></author><author><name sortKey="Lebon, J" uniqKey="Lebon J">J Lebon</name></author><author><name sortKey="Tessier, D" uniqKey="Tessier D">D Tessier</name></author><author><name sortKey="Dionne, Ij" uniqKey="Dionne I">IJ Dionne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ryan, As" uniqKey="Ryan A">AS Ryan</name></author><author><name sortKey="Nicklas, Bj" uniqKey="Nicklas B">BJ Nicklas</name></author><author><name sortKey="Berman, Dm" uniqKey="Berman D">DM Berman</name></author><author><name sortKey="Elahi, D" uniqKey="Elahi D">D Elahi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yaccoby, S" uniqKey="Yaccoby S">S Yaccoby</name></author><author><name sortKey="Ling, W" uniqKey="Ling W">W Ling</name></author><author><name sortKey="Zhan, F" uniqKey="Zhan F">F Zhan</name></author><author><name sortKey="Walker, R" uniqKey="Walker R">R Walker</name></author><author><name sortKey="Barlogie, B" uniqKey="Barlogie B">B Barlogie</name></author><author><name sortKey="Shaughnessy, Jd" uniqKey="Shaughnessy J">JD Shaughnessy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, F" uniqKey="Zhou F">F Zhou</name></author><author><name sortKey="Meng, S" uniqKey="Meng S">S Meng</name></author><author><name sortKey="Song, H" uniqKey="Song H">H Song</name></author><author><name sortKey="Claret, Fx" uniqKey="Claret F">FX Claret</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Capietto, Ah" uniqKey="Capietto A">AH Capietto</name></author><author><name sortKey="Kim, S" uniqKey="Kim S">S Kim</name></author><author><name sortKey="Sanford, De" uniqKey="Sanford D">DE Sanford</name></author><author><name sortKey="Linehan, Dc" uniqKey="Linehan D">DC Linehan</name></author><author><name sortKey="Hikida, M" uniqKey="Hikida M">M Hikida</name></author><author><name sortKey="Kumosaki, T" uniqKey="Kumosaki T">T Kumosaki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yamabuki, T" uniqKey="Yamabuki T">T Yamabuki</name></author><author><name sortKey="Takano, A" uniqKey="Takano A">A Takano</name></author><author><name sortKey="Hayama, S" uniqKey="Hayama S">S Hayama</name></author><author><name sortKey="Ishikawa, N" uniqKey="Ishikawa N">N Ishikawa</name></author><author><name sortKey="Kato, T" uniqKey="Kato T">T Kato</name></author><author><name sortKey="Miyamoto, M" uniqKey="Miyamoto M">M Miyamoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Tang, W" uniqKey="Tang W">W Tang</name></author><author><name sortKey="Xie, L" uniqKey="Xie L">L Xie</name></author><author><name sortKey="Wang, J" uniqKey="Wang J">J Wang</name></author><author><name sortKey="Deng, Y" uniqKey="Deng Y">Y Deng</name></author><author><name sortKey="Peng, Q" uniqKey="Peng Q">Q Peng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spillane, M" uniqKey="Spillane M">M Spillane</name></author><author><name sortKey="Schwarz, N" uniqKey="Schwarz N">N Schwarz</name></author><author><name sortKey="Willoughby, Ds" uniqKey="Willoughby D">DS Willoughby</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xu, X" uniqKey="Xu X">X Xu</name></author><author><name sortKey="Zhan, M" uniqKey="Zhan M">M Zhan</name></author><author><name sortKey="Duan, W" uniqKey="Duan W">W Duan</name></author><author><name sortKey="Prabhu, V" uniqKey="Prabhu V">V Prabhu</name></author><author><name sortKey="Brenneman, R" uniqKey="Brenneman R">R Brenneman</name></author><author><name sortKey="Wood, W" uniqKey="Wood W">W Wood</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Staal, Fj" uniqKey="Staal F">FJ Staal</name></author><author><name sortKey="Luis, Tc" uniqKey="Luis T">TC Luis</name></author><author><name sortKey="Tiemessen, Mm" uniqKey="Tiemessen M">MM Tiemessen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gattinoni, L" uniqKey="Gattinoni L">L Gattinoni</name></author><author><name sortKey="Ji, Y" uniqKey="Ji Y">Y Ji</name></author><author><name sortKey="Restifo, Np" uniqKey="Restifo N">NP Restifo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cao Dinh, H" uniqKey="Cao Dinh H">H Cao Dinh</name></author><author><name sortKey="Beyer, I" uniqKey="Beyer I">I Beyer</name></author><author><name sortKey="Mets, T" uniqKey="Mets T">T Mets</name></author><author><name sortKey="Onyema, Oo" uniqKey="Onyema O">OO Onyema</name></author><author><name sortKey="Njemini, R" uniqKey="Njemini R">R Njemini</name></author><author><name sortKey="Renmans, W" uniqKey="Renmans W">W Renmans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Veeck, J" uniqKey="Veeck J">J Veeck</name></author><author><name sortKey="Niederacher, D" uniqKey="Niederacher D">D Niederacher</name></author><author><name sortKey="An, H" uniqKey="An H">H An</name></author><author><name sortKey="Klopocki, E" uniqKey="Klopocki E">E Klopocki</name></author><author><name sortKey="Wiesmann, F" uniqKey="Wiesmann F">F Wiesmann</name></author><author><name sortKey="Betz, B" uniqKey="Betz B">B Betz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suzuki, H" uniqKey="Suzuki H">H Suzuki</name></author><author><name sortKey="Toyota, M" uniqKey="Toyota M">M Toyota</name></author><author><name sortKey="Carraway, H" uniqKey="Carraway H">H Carraway</name></author><author><name sortKey="Gabrielson, E" uniqKey="Gabrielson E">E Gabrielson</name></author><author><name sortKey="Ohmura, T" uniqKey="Ohmura T">T Ohmura</name></author><author><name sortKey="Fujikane, T" uniqKey="Fujikane T">T Fujikane</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klopocki, E" uniqKey="Klopocki E">E Klopocki</name></author><author><name sortKey="Kristiansen, G" uniqKey="Kristiansen G">G Kristiansen</name></author><author><name sortKey="Wild, Pj" uniqKey="Wild P">PJ Wild</name></author><author><name sortKey="Klaman, I" uniqKey="Klaman I">I Klaman</name></author><author><name sortKey="Castanos Velez, E" uniqKey="Castanos Velez E">E Castanos-Velez</name></author><author><name sortKey="Singer, G" uniqKey="Singer G">G Singer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lagathu, C" uniqKey="Lagathu C">C Lagathu</name></author><author><name sortKey="Christodoulides, C" uniqKey="Christodoulides C">C Christodoulides</name></author><author><name sortKey="Tan, Cy" uniqKey="Tan C">CY Tan</name></author><author><name sortKey="Virtue, S" uniqKey="Virtue S">S Virtue</name></author><author><name sortKey="Laudes, M" uniqKey="Laudes M">M Laudes</name></author><author><name sortKey="Campbell, M" uniqKey="Campbell M">M Campbell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, M" uniqKey="Wang M">M Wang</name></author><author><name sortKey="Cheng, N" uniqKey="Cheng N">N Cheng</name></author><author><name sortKey="Zheng, S" uniqKey="Zheng S">S Zheng</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author><author><name sortKey="Hu, X" uniqKey="Hu X">X Hu</name></author><author><name sortKey="Ren, X" uniqKey="Ren X">X Ren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bhandari, R" uniqKey="Bhandari R">R Bhandari</name></author><author><name sortKey="Kelley, Ga" uniqKey="Kelley G">GA Kelley</name></author><author><name sortKey="Hartley, Ta" uniqKey="Hartley T">TA Hartley</name></author><author><name sortKey="Rockett, Ir" uniqKey="Rockett I">IR Rockett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mauro, L" uniqKey="Mauro L">L Mauro</name></author><author><name sortKey="Naimo, Gd" uniqKey="Naimo G">GD Naimo</name></author><author><name sortKey="Ricchio, E" uniqKey="Ricchio E">E Ricchio</name></author><author><name sortKey="Panno, Ml" uniqKey="Panno M">ML Panno</name></author><author><name sortKey="Ando, S" uniqKey="Ando S">S Ando</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Giannopoulou, I" uniqKey="Giannopoulou I">I Giannopoulou</name></author><author><name sortKey="Fernhall, B" uniqKey="Fernhall B">B Fernhall</name></author><author><name sortKey="Carhart, R" uniqKey="Carhart R">R Carhart</name></author><author><name sortKey="Weinstock, Rs" uniqKey="Weinstock R">RS Weinstock</name></author><author><name sortKey="Baynard, T" uniqKey="Baynard T">T Baynard</name></author><author><name sortKey="Figueroa, A" uniqKey="Figueroa A">A Figueroa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Befort, Ca" uniqKey="Befort C">CA Befort</name></author><author><name sortKey="Klemp, Jr" uniqKey="Klemp J">JR Klemp</name></author><author><name sortKey="Austin, Hl" uniqKey="Austin H">HL Austin</name></author><author><name sortKey="Perri, Mg" uniqKey="Perri M">MG Perri</name></author><author><name sortKey="Schmitz, Kh" uniqKey="Schmitz K">KH Schmitz</name></author><author><name sortKey="Sullivan, Dk" uniqKey="Sullivan D">DK Sullivan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Decensi, A" uniqKey="Decensi A">A DeCensi</name></author><author><name sortKey="Gennari, A" uniqKey="Gennari A">A Gennari</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28178355</article-id><article-id pub-id-type="pmc">5298304</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0171771</article-id><article-id pub-id-type="publisher-id">PONE-D-16-31766</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Public and Occupational Health</subject><subj-group><subject>Physical Activity</subject><subj-group><subject>Physical Fitness</subject><subj-group><subject>Exercise</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Sports and Exercise Medicine</subject><subj-group><subject>Exercise</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Sports Science</subject><subj-group><subject>Sports and Exercise Medicine</subject><subj-group><subject>Exercise</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Breast Tumors</subject><subj-group><subject>Breast Cancer</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Public and Occupational Health</subject><subj-group><subject>Physical Activity</subject><subj-group><subject>Physical Fitness</subject><subj-group><subject>Exercise</subject><subj-group><subject>Strength Training</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Sports and Exercise Medicine</subject><subj-group><subject>Exercise</subject><subj-group><subject>Strength Training</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Sports Science</subject><subj-group><subject>Sports and Exercise Medicine</subject><subj-group><subject>Exercise</subject><subj-group><subject>Strength Training</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Cell Signaling</subject><subj-group><subject>Signaling Cascades</subject><subj-group><subject>WNT Signaling Cascade</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Public and Occupational Health</subject><subj-group><subject>Physical Activity</subject><subj-group><subject>Physical Fitness</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Biomarkers</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Sports and Exercise Medicine</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Sports Science</subject><subj-group><subject>Sports and Exercise Medicine</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Adipose Tissue</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Adipose Tissue</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial</article-title><alt-title alt-title-type="running-head">Exercise training and Wnt-Antagonists in breast cancer survivors</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kim</surname><given-names>Tae Ho</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-4047-1128</contrib-id><name><surname>Chang</surname><given-names>Jae Seung</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Kyu-Sang</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Jeeyeon</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Nahyun</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Jong In</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kong</surname><given-names>In Deok</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Yonsei Institute of Sports Science & Exercise Medicine, Wonju, Republic of Korea</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Nursing Science, Kyungsung University, Busan, Republic of Korea</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Basic Nursing Science, Keimyung University College of Nursing, Daegu, Republic of Korea</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Tagliabue</surname><given-names>Elda</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Fondazione IRCCS Istituto Nazionale dei Tumori, ITALY</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p><list list-type="simple"><list-item><p><bold>Conceptualization:</bold> THK and JSC.</p></list-item><list-item><p><bold>Formal analysis:</bold> THK and JSC.</p></list-item><list-item><p><bold>Investigation:</bold> THK, JSC and JP.</p></list-item><list-item><p><bold>Methodology:</bold> JSC and IDK.</p></list-item><list-item><p><bold>Project administration:</bold> JSC and IDK.</p></list-item><list-item><p><bold>Resources:</bold> JP, NK and JIL.</p></list-item><list-item><p><bold>Visualization:</bold> JSC.</p></list-item><list-item><p><bold>Writing – original draft:</bold> THK.</p></list-item><list-item><p><bold>Writing – review & editing:</bold> JSC, KP and IDK.</p></list-item></list></p></fn><corresp id="cor001">* E-mail: <email>kong@yonsei.ac.kr</email></corresp></author-notes><pub-date pub-type="epub"><day>8</day><month>2</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>2</issue><elocation-id>e0171771</elocation-id><history><date date-type="received"><day>26</day><month>9</month><year>2016</year></date><date date-type="accepted"><day>25</day><month>1</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Kim et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Kim et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0171771.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Wingless and integration site growth factor (Wnt) signaling is a tumorigenesis-related signaling pathway. Dickkpof-1 (DKK1) and secreted frizzled-related protein-1 (SFRP1) are endogenous negative regulators of Wnt/β-catenin signaling. Accumulating evidence indicates that higher serum levels of DKK1 are correlated with poor prognosis of various types of cancer. Here, we investigated whether exercise training causes changes in the serum levels of DKK1 and SFRP1 in patients with breast cancer.</p></sec><sec id="sec002"><title>Methods</title><p>Twenty-four breast cancer survivors, after chemo- or radiotherapy, participated in this single-blind randomized, controlled pilot study. Subjects were randomized to either an exercise program or a control group for 12 weeks and completed pre- and post-training tests for health-related fitness and body composition as well as blood biomarkers. The serum levels of DKK1 and SFRP1 were measured using enzyme-linked immunosorbent assay as the primary outcome.</p></sec><sec id="sec003"><title>Results</title><p>Exercise training for 12 weeks remarkably increased muscle strength, endurance, and flexibility and decreased body fat percentage, waist circumference, and visceral fat area (all <italic>p</italic> < 0.05). Exercise training lowered serum insulin levels and leptin/adiponectin ratios (all <italic>p</italic> < 0.05). The levels of DKK1 and SFRP1 were also significantly decreased by exercise training in breast cancer survivors (all <italic>p</italic> < 0.01).</p></sec><sec id="sec004"><title>Conclusions</title><p>Our results indicate that DKK1 and SFRP1 may be potentially useful biomarkers for evaluating the beneficial effects of long-term exercise on physical fitness and metabolism as well as the prognosis of patients with cancer.</p></sec><sec id="sec005"><title>Trial registration</title><p>ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02895178">NCT02895178</ext-link></p></sec></abstract><funding-group><funding-statement>The authors received no specific funding for this work.</funding-statement></funding-group><counts><fig-count count="2"></fig-count><table-count count="2"></table-count><page-count count="13"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data availability</meta-name><meta-value>Because the data contains medical privacy of the participants, there are ethical and legal restrictions on sharing the data publicly. Data are available from the Medical Ethics Committee of Yonsei University Wonju College of Medicine for researchers who meet the criteria for access to confidential data. The contact information for the representative of the ethics committee is as follow: Byung-Il Yeh, <email>mia1@yonsei.ac.kr</email></meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data availability</title><p>Because the data contains medical privacy of the participants, there are ethical and legal restrictions on sharing the data publicly. Data are available from the Medical Ethics Committee of Yonsei University Wonju College of Medicine for researchers who meet the criteria for access to confidential data. The contact information for the representative of the ethics committee is as follow: Byung-Il Yeh, <email>mia1@yonsei.ac.kr</email></p></notes></front><body><sec sec-type="intro" id="sec006"><title>Introduction</title><p>Patients and survivors of breast cancer present impaired physical fitness and various complications including acute and chronic pain, severe fatigue, limited range of motion, and bone loss attributable to anti-cancer treatments [<xref rid="pone.0171771.ref001" ref-type="bibr">1</xref>,<xref rid="pone.0171771.ref002" ref-type="bibr">2</xref>]. Therefore, regular exercise during and following cancer treatments has been recommended to enhance physical capabilities and reduce the severity of side-effects of treatments, leading to an improved quality of life [<xref rid="pone.0171771.ref002" ref-type="bibr">2</xref>–<xref rid="pone.0171771.ref004" ref-type="bibr">4</xref>]. Despite the known general benefits to cancer patients, the effects of exercise on the initiation and progression of the tumor itself remain unclear.</p><p>Wingless and integration site growth factor (Wnt) signaling is one of the major tumorigenesis-related signaling pathways [<xref rid="pone.0171771.ref005" ref-type="bibr">5</xref>]. Secreted Wnt and its downstream effectors regulate critical processes during tumor growth and metastasis [<xref rid="pone.0171771.ref006" ref-type="bibr">6</xref>]. Additionally, Wnt mutations are associated with breast cancer and other common types of cancer [<xref rid="pone.0171771.ref005" ref-type="bibr">5</xref>,<xref rid="pone.0171771.ref006" ref-type="bibr">6</xref>]. Dysregulated Wnt signaling has been detected in carcinogenesis of the mammary gland [<xref rid="pone.0171771.ref007" ref-type="bibr">7</xref>–<xref rid="pone.0171771.ref009" ref-type="bibr">9</xref>]. The molecular mechanisms of Wnt signaling are categorized into β-catenin-dependent (canonical) and -independent (non-canonical) pathways [<xref rid="pone.0171771.ref010" ref-type="bibr">10</xref>,<xref rid="pone.0171771.ref011" ref-type="bibr">11</xref>]. The canonical pathway is activated by the binding of Wnt ligands to Frizzled receptors and low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) on the cell membrane, promoting the stabilization and transcriptional activity of β-catenin [<xref rid="pone.0171771.ref009" ref-type="bibr">9</xref>,<xref rid="pone.0171771.ref012" ref-type="bibr">12</xref>]. Non-canonical Wnt signaling is composed of two well-characterized pathways: the planar cell polarity pathway and the Wnt/Ca<sup>2+</sup> pathway [<xref rid="pone.0171771.ref013" ref-type="bibr">13</xref>–<xref rid="pone.0171771.ref015" ref-type="bibr">15</xref>].</p><p>For the past two decades, a number of endogenous modulators of Wnt signaling have been identified. Among them, Dickkpof-1 (DKK1) is a soluble inhibitor of the Wnt signaling pathway, which acts by binding to LRP5/6 and Kremen protein to induce endocytosis, causing proteosomal degradation of β-catenin [<xref rid="pone.0171771.ref009" ref-type="bibr">9</xref>,<xref rid="pone.0171771.ref016" ref-type="bibr">16</xref>,<xref rid="pone.0171771.ref017" ref-type="bibr">17</xref>]. Secreted frizzled-related protein-1 (SFRP1) blocks Wnt signaling by binding to Wnt ligands or Frizzled receptors [<xref rid="pone.0171771.ref009" ref-type="bibr">9</xref>]. DKK1 can inhibit only the canonical pathway, whereas SFRP1 can antagonize both canonical and non-canonical Wnt signaling [<xref rid="pone.0171771.ref018" ref-type="bibr">18</xref>–<xref rid="pone.0171771.ref020" ref-type="bibr">20</xref>]. Paradoxically, DKK1 levels were found to be markedly increased in patients with breast cancer compared with both, women in complete remission and healthy controls [<xref rid="pone.0171771.ref021" ref-type="bibr">21</xref>,<xref rid="pone.0171771.ref022" ref-type="bibr">22</xref>]. Higher serum levels of DKK1 were correlated with bone metastasis of breast cancer and its mortality [<xref rid="pone.0171771.ref016" ref-type="bibr">16</xref>,<xref rid="pone.0171771.ref017" ref-type="bibr">17</xref>]. A correlation between high DKK1 and poor prognosis was also observed in serological samples from patients with pancreatic, prostate, stomach, liver, and lung cancers regardless of the presence of metastatic dissemination to the bone [<xref rid="pone.0171771.ref023" ref-type="bibr">23</xref>–<xref rid="pone.0171771.ref025" ref-type="bibr">25</xref>]. Furthermore, inhibition of DKK1 by neutralization decreased tumor growth [<xref rid="pone.0171771.ref025" ref-type="bibr">25</xref>]. Therefore, the regulation of DKK1 may be a therapeutic target in the development of anti-cancer therapy.</p><p>A recent study reported that serum DKK1 levels were significantly decreased after participation in an ultradistance marathon [<xref rid="pone.0171771.ref026" ref-type="bibr">26</xref>]. An animal study also showed that sedentary conditions elevated DKK1 expression in brain tissue, indirectly showing that physical activity downregulates DKK1 [<xref rid="pone.0171771.ref027" ref-type="bibr">27</xref>]. In this study, we detected reduced serum levels of DKK1 and SFRP1 in breast cancer survivors following a long-term (12-week) exercise program. These changes were accompanied by improved physical fitness and biomarker levels related to metabolic conditions, indicating the possible involvement of Wnt antagonists in the beneficial effects of exercise.</p></sec><sec sec-type="materials|methods" id="sec007"><title>Methods</title><p>The supporting study protocol and CONSORT checklist are available as supporting information; see <xref ref-type="supplementary-material" rid="pone.0171771.s001">S1</xref> and <xref ref-type="supplementary-material" rid="pone.0171771.s002">S2</xref> Texts (original language and English versions) and <xref ref-type="supplementary-material" rid="pone.0171771.s003">S1 Table</xref>.</p><sec id="sec008"><title>Study participants</title><p>Survivors of breast cancer who visited the hemato-oncology center of Wonju Severance Christian Hospital were recruited between June 1 and December 31, 2014. They were eligible to participate in this study if they met the following criteria, with medical clearance from their oncologist: (1) diagnosed with stage I–III breast cancer, (2) ≥ 6 months after treatments with radio- and/or chemotherapy subsequent to surgery, (3) absence of metastatic diseases and other cancers, (4) < 60 min per week of physical activity including resistance exercise in the past 6 months, (5) absence of cardiovascular and respiratory diseases, and (6) no contraindicated medications and comorbidities that prohibit participation in a moderate exercise program. After the intervention period of 12 weeks, the study participants were followed-up between September 16, 2014 and April 30, 2015. A total of 45 subjects were included in the final analysis (exercise group, n = 11; non-exercise control group, n = 13; age-matched healthy women, n = 21). All procedures and informed consent document were reviewed and approved by the Medical Ethics Committee of Yonsei University Wonju College of Medicine, Korea (YWMR-14-0-042; approval date: May 23, 2014). Written informed consent was obtained from all participants included in the study. The study was conducted in accordance with the Declaration of Helsinki principles.</p></sec><sec id="sec009"><title>Design and procedures</title><p>Treatment history and menstrual status were obtained from the clinical reports of the hemato-oncology center with the consent of participants. Demographic characteristics were collected through self-reports (<xref ref-type="table" rid="pone.0171771.t001">Table 1</xref>). Measurements were conducted at baseline and after 12 weeks exercise training and included anthropometry, body composition, health–related fitness levels, and a blood sample. As this was a randomized pilot study, a sample size calculation was not performed. Participant recruitment and enrollment began after ethical approval, but the protocol of this pilot trial was retrospectively registered on ClinicalTrials. gov (identification number: NCT02895178), as the authors were unaware of the journal requirements. The authors confirm that all ongoing and related trials for this exercise intervention are registered.</p><table-wrap id="pone.0171771.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0171771.t001</object-id><label>Table 1</label><caption><title>Baseline demographic characteristics.</title></caption><alternatives><graphic id="pone.0171771.t001g" xlink:href="pone.0171771.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="justify" rowspan="1" colspan="1">Variable</th><th align="center" rowspan="1" colspan="1">Control group</th><th align="center" rowspan="1" colspan="1">Exercise group</th><th align="center" rowspan="1" colspan="1">Total participants</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age (years)*</td><td align="center" rowspan="1" colspan="1">49.3 (4.8)</td><td align="center" rowspan="1" colspan="1">56.0 (6.5)</td><td align="center" rowspan="1" colspan="1">52.4 (6.5)</td></tr><tr><td align="left" rowspan="1" colspan="1">Height (cm)*</td><td align="center" rowspan="1" colspan="1">156.1 (3.7)</td><td align="center" rowspan="1" colspan="1">157.0 (5.0)</td><td align="center" rowspan="1" colspan="1">156.5 (4.3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Weight (kg)*</td><td align="center" rowspan="1" colspan="1">61.0 (11.9)</td><td align="center" rowspan="1" colspan="1">59.1 (7.1)</td><td align="center" rowspan="1" colspan="1">60.2 (9.8)</td></tr><tr><td align="left" rowspan="1" colspan="1">BMI (kg/m<sup>2</sup>)*</td><td align="center" rowspan="1" colspan="1">25.0 (4.7)</td><td align="center" rowspan="1" colspan="1">23.9 (2.7)</td><td align="center" rowspan="1" colspan="1">24.5 (3.9)</td></tr><tr><td align="left" rowspan="1" colspan="1">Body fat (%)*</td><td align="center" rowspan="1" colspan="1">34.6 (7.4)</td><td align="center" rowspan="1" colspan="1">36.1 (4.6)</td><td align="center" rowspan="1" colspan="1">35.3 (6.2)</td></tr><tr><td align="left" rowspan="1" colspan="1">Married<sup>†</sup></td><td align="center" rowspan="1" colspan="1">13 (100)</td><td align="center" rowspan="1" colspan="1">11 (100)</td><td align="center" rowspan="1" colspan="1">24 (100)</td></tr><tr><td align="left" rowspan="1" colspan="1">Graduate university<sup>†</sup></td><td align="center" rowspan="1" colspan="1">5 (38.4)</td><td align="center" rowspan="1" colspan="1">4 (36.3)</td><td align="center" rowspan="1" colspan="1">9 (37.5)</td></tr><tr><td align="left" rowspan="1" colspan="1">Current smoker<sup>†</sup></td><td align="center" rowspan="1" colspan="1">0 (0)</td><td align="center" rowspan="1" colspan="1">0 (0)</td><td align="center" rowspan="1" colspan="1">0 (0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Postmenopausal<sup>†</sup></td><td align="center" rowspan="1" colspan="1">13 (100)</td><td align="center" rowspan="1" colspan="1">10 (91)</td><td align="center" rowspan="1" colspan="1">23 (95.8)</td></tr><tr><td align="left" rowspan="1" colspan="1">Mastectomy<sup>†</sup></td><td align="center" rowspan="1" colspan="1">2 (15.4)</td><td align="center" rowspan="1" colspan="1">2 (18.2)</td><td align="center" rowspan="1" colspan="1">4 (16.7)</td></tr><tr><td align="left" rowspan="1" colspan="1">Lumpectomy<sup>†</sup></td><td align="center" rowspan="1" colspan="1">11 (84.6)</td><td align="center" rowspan="1" colspan="1">9 (81.8)</td><td align="center" rowspan="1" colspan="1">20 (83.3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Radiotherapy<sup>†</sup></td><td align="center" rowspan="1" colspan="1">12 (92.3)</td><td align="center" rowspan="1" colspan="1">10 (90.9)</td><td align="center" rowspan="1" colspan="1">22 (91.6)</td></tr><tr><td align="left" rowspan="1" colspan="1">Chemotherapy<sup>†</sup></td><td align="center" rowspan="1" colspan="1">12 (92.3)</td><td align="center" rowspan="1" colspan="1">9 (81.8)</td><td align="center" rowspan="1" colspan="1">21 (87.5)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>Data are presented as *mean (standard deviation) or <sup>†</sup>n (%).</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec010"><title>Randomization and blinding</title><p>Following baseline assessments, thirty participants were randomly assigned to either an exercise intervention group or a control group using a sealed, computer random number generator with an allocation ratio of 1 to 1. Four research staff members who were unaware of group assignment performed all outcome assessments. The statistician was unaware of treatment allocation until completion of the statistical analyses. Participants were not blinded to their assignment but were unaware of main outcome measures and were instructed to avoid mentioning anything regarding their study experience to the assessors.</p></sec><sec id="sec011"><title>Outcome measures</title><p>The primary outcome measures were serum levels of DKK1 and SFRP1. The secondary outcome measures included anthropometric and body composition indices, health-related fitness parameters, and serological biomarkers.</p><sec id="sec012"><title>Biomarker measurements</title><p>Blood samples were drawn from the antecubital vein and collected in serum separation tubes and the tubes were centrifuged at 3000 rpm (1,000 × <italic>g</italic>) for 10 min. Serum samples were collected and immediately stored at -80°C until analysis. Commercially available enzyme linked immune sorbent assay kits were used to measure the serum levels of leptin (DLP00, R&D Systems, Minneapolis, MN, USA), adiponectin (DRP300), DKK1 (DKK100), and SFRP1 (SEF880Hu, USCN Life Science, Wuhan, China). Serum insulin and high-sensitivity C-reactive protein were measured by electrochemiluminescence immunoassay (Roche cobas 8000-e602 module, Roche Diagnostics, Basel, Switzerland) and latex-enhanced immunoturbidimetric assay (Roche-Hitachi cobas c system, Roche Diagnostics), respectively.</p></sec><sec id="sec013"><title>Anthropometry and body composition measurements</title><p>\Body weight and height were measured to the nearest 0.1 kg and 0.1 cm, respectively, and then body mass index was calculated as body weight divided by height in meters squared (kg/m<sup>2</sup>). Waist circumference was measured at the midpoint between the lower rib margin and iliac crest and was expressed in centimeters. Body fat percentage, visceral fat area, and arm circumferences were measured by multifrequency bioelectrical impedance analysis (Inbody 720, Biospace, Centennial, CO, USA).</p></sec><sec id="sec014"><title>Health-related physical fitness measurements</title><p>Subjects were evaluated for health-related components of fitness such as standing long jump, handgrip strength, sit-up, 10-m shuttle run, 20-m pacer, and sit and reach. The test parameters indicate individual abilities of physical fitness regarding muscular power, strength and endurance, agility, aerobic capacity, and flexibility.</p></sec></sec><sec id="sec015"><title>Exercise intervention group</title><p>The exercise training program was designed following the American College of Sports Medicine’s guide to exercise and cancer survivorship (exercise intensity, frequency, time, and type), and was performed at least thrice weekly for 12 weeks, under the direct supervision of exercise physiologists [<xref rid="pone.0171771.ref028" ref-type="bibr">28</xref>]. Exercise training was conducted with the Borg’s ratings of perceived exertion (RPE) scale within the range of RPE 11–13 that was gradually and moderately increased at 4-week intervals until reaching a rating of 13–15 [<xref rid="pone.0171771.ref029" ref-type="bibr">29</xref>]. Each session began with a warm-up consisting whole body stretching and flexibility exercises for shoulder muscle stiffness such as finger climbing, shoulder glides (inferior, anterior, and posterior), and pendulum exercises for 10 min. The exercise program incorporated step aerobics on 17-cm (6.7-inch) platforms for 20 min followed by the strength training using body weight and elastic bands consisting of shoulder press, black burn exercise, wall push-up, biceps curl-up, plank exercise, leg bridge, squat, and calf raise for 20 min. The strength training was designed to begin with one set for the first two weeks, and the set number was increased every two weeks to finally achieve three sets of each exercise performing 12‒16 repetitions to volitional fatigue per set. The exercise intensity and the resistance of elastic band were progressively increased to maintain this range of repetition. At the end of the session, subjects performed cool-down involving easy walking and stretching exercises for 10 min.</p></sec><sec id="sec016"><title>Control group</title><p>Subjects in the control group were instructed to maintain their routine physical activities and not to participate any new exercise programs during the 12-weeks study period. Afterward, the subjects who completed both pre- and post-test received an opportunity to participate in the same exercise program that intervention group had performed.</p></sec><sec id="sec017"><title>Age-matched healthy women</title><p>Twenty-one age-matched healthy women (mean ± SD, 51.7 ± 5.9 years) were included in this study, in order to compare the basal serum levels of DKK1 between breast cancer survivors and healthy women without a history of breast cancer. The average BMI and body fat percentage of the healthy volunteers were 23.8 ± 2.5 kg/m<sup>2</sup> and 33.6 ± 6.7%, respectively. All healthy volunteers were married, and non-smokers. Most of the demographic characteristics of the subject corresponded closely to those of breast cancer survivors.</p></sec><sec id="sec018"><title>Data analysis</title><p>All data were analyzed using SPSS 22.0 software (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were calculated to identify the means and standard deviations or standard errors of mean (SEM). A Fisher’s exact test was used to assess the homogeneity of age distribution between the two groups. Paired <italic>t</italic>-test or Wilcoxon signed-rank test were used to compare the levels of health-related fitness, body composition, and serum biomarkers between before and after training. Statistical significance was set at <italic>p</italic> < 0.05.</p></sec></sec><sec sec-type="results" id="sec019"><title>Results</title><p>The study flow diagram for the recruitment, participation, and dropout of breast cancer survivors is presented in <xref ref-type="fig" rid="pone.0171771.g001">Fig 1</xref>. The final dropout rate after 12 weeks in the exercise group was 26% and that in the control group was 13%. Of the 30 women who were eligible for inclusion in this study, six were excluded from final analysis. The reasons for non-inclusion in the analysis were as follows: three women were absent at post-test, two did not fulfill the required exercise sessions of at least three times per week, and one withdrew from the exercise program for personal reasons.</p><fig id="pone.0171771.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0171771.g001</object-id><label>Fig 1</label><caption><title>Study flow diagram.</title><p>This flow diagram shows the study protocol and sequence of events in this study.</p></caption><graphic xlink:href="pone.0171771.g001"></graphic></fig><p>The Fisher’s exact test indicated no significant difference in age distribution between exercise group and control group (<italic>p</italic> = 0.150). Exercise training for 12 weeks resulted in noticeable changes in anthropometry and body composition. Waist circumference was decreased by 2.8% (<italic>p</italic> = 0.041) and total body fat and visceral fat area were reduced by 5.5% (<italic>p</italic> = 0.005) and 5% (<italic>p</italic> = 0.010), respectively, through exercise training (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>). Exercise training decreased right (<italic>p</italic> = 0.027) and left (<italic>p</italic> = 0.056) arm circumferences, reflecting a lymphedema status (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>). Similarly, overall health-related physical fitness was also improved in the exercise group, but no changes occurred in the non-exercise control group. Muscular strength measured by a handheld dynamometer and its relative value (handgrip strength to weight ratio) were significantly increased by 14% (<italic>p</italic> = 0.043) and 16% (<italic>p</italic> = 0.039), respectively, through the exercise training program (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>). In addition, muscular endurance measured in the sit-up test (<italic>p</italic> = 0.025) and flexibility assessed in the sit and reach (<italic>p</italic> = 0.010) tests were enhanced through exercise training (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>). Muscular power, agility, and aerobic capacity remained unchanged in both groups after 12 weeks (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>).</p><table-wrap id="pone.0171771.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0171771.t002</object-id><label>Table 2</label><caption><title>Changes in anthropometrics, body composition, health-related fitness, and blood variables between pre- and post-exercise training.</title></caption><alternatives><graphic id="pone.0171771.t002g" xlink:href="pone.0171771.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="justify" rowspan="1" colspan="1"></th><th align="center" colspan="3" rowspan="1">Control group</th><th align="center" colspan="3" rowspan="1">Exercise group</th></tr><tr><th align="justify" rowspan="1" colspan="1">Variables</th><th align="center" rowspan="1" colspan="1">Pre</th><th align="center" rowspan="1" colspan="1">Post</th><th align="center" rowspan="1" colspan="1"><italic>p</italic>-value</th><th align="center" rowspan="1" colspan="1">Pre</th><th align="center" rowspan="1" colspan="1">Post</th><th align="center" rowspan="1" colspan="1"><italic>p</italic>-value</th></tr></thead><tbody><tr><td align="left" colspan="7" rowspan="1">Anthropometry</td></tr><tr><td align="left" rowspan="1" colspan="1">Weight (kg)</td><td align="center" rowspan="1" colspan="1">61.0 (11.9)</td><td align="center" rowspan="1" colspan="1">61.6 (12.1)</td><td align="center" rowspan="1" colspan="1">0.490</td><td align="center" rowspan="1" colspan="1">59.2 (7.1)</td><td align="center" rowspan="1" colspan="1">58.4 (8.0)</td><td align="center" rowspan="1" colspan="1">0.150</td></tr><tr><td align="left" rowspan="1" colspan="1">Waist circumference (cm)</td><td align="center" rowspan="1" colspan="1">82.0 (13.7)</td><td align="center" rowspan="1" colspan="1">81.4 (15.5)</td><td align="center" rowspan="1" colspan="1">0.225</td><td align="center" rowspan="1" colspan="1">81.6 (7.1)</td><td align="center" rowspan="1" colspan="1">79.4 (6.7)</td><td align="center" rowspan="1" colspan="1">0.041</td></tr><tr><td align="left" rowspan="1" colspan="1">Right-arm circumference (cm)</td><td align="center" rowspan="1" colspan="1">30.4 (4.1)</td><td align="center" rowspan="1" colspan="1">30.6 (4.0)</td><td align="center" rowspan="1" colspan="1">0.205</td><td align="center" rowspan="1" colspan="1">29.2 (2.0)</td><td align="center" rowspan="1" colspan="1">28.7 (1.7)</td><td align="center" rowspan="1" colspan="1">0.027</td></tr><tr><td align="left" rowspan="1" colspan="1">Left-arm circumference(cm)</td><td align="center" rowspan="1" colspan="1">30.2 (3.9)</td><td align="center" rowspan="1" colspan="1">30.4 (4.0)</td><td align="center" rowspan="1" colspan="1">0.073</td><td align="center" rowspan="1" colspan="1">29.1 (2.0)</td><td align="center" rowspan="1" colspan="1">28.7 (1.7)</td><td align="center" rowspan="1" colspan="1">0.056</td></tr><tr><td align="left" colspan="7" rowspan="1">Body composition</td></tr><tr><td align="left" rowspan="1" colspan="1">Body fat (%)</td><td align="center" rowspan="1" colspan="1">34.6 (7.4)</td><td align="center" rowspan="1" colspan="1">36.2 (6.8)</td><td align="center" rowspan="1" colspan="1">0.074</td><td align="center" rowspan="1" colspan="1">36.1 (4.6)</td><td align="center" rowspan="1" colspan="1">34.1 (5.5)</td><td align="center" rowspan="1" colspan="1">0.005</td></tr><tr><td align="left" rowspan="1" colspan="1">Visceral fat area (cm<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">88.7 (30.4)</td><td align="center" rowspan="1" colspan="1">90.3 (32.3)</td><td align="center" rowspan="1" colspan="1">0.453</td><td align="center" rowspan="1" colspan="1">86.5 (20.4)</td><td align="center" rowspan="1" colspan="1">82.2 (21.4)</td><td align="center" rowspan="1" colspan="1">0.010</td></tr><tr><td align="left" colspan="7" rowspan="1">Health-related fitness</td></tr><tr><td align="left" rowspan="1" colspan="1">Handgrip strength (kg)</td><td align="center" rowspan="1" colspan="1">25.2 (3.3)</td><td align="center" rowspan="1" colspan="1">24.9 (4.4)</td><td align="center" rowspan="1" colspan="1">0.701</td><td align="center" rowspan="1" colspan="1">22.3 (5.1)</td><td align="center" rowspan="1" colspan="1">25.4 (3.1)</td><td align="center" rowspan="1" colspan="1">0.043</td></tr><tr><td align="left" rowspan="1" colspan="1">Relative handgrip strength ratio</td><td align="center" rowspan="1" colspan="1">42.2 (6.7)</td><td align="center" rowspan="1" colspan="1">41.7 (8.3)</td><td align="center" rowspan="1" colspan="1">0.647</td><td align="center" rowspan="1" colspan="1">37.8 (1.4)</td><td align="center" rowspan="1" colspan="1">43.8 (8.9)</td><td align="center" rowspan="1" colspan="1">0.039</td></tr><tr><td align="left" rowspan="1" colspan="1">Sit-up (n)</td><td align="center" rowspan="1" colspan="1">13.2 (7.7)</td><td align="center" rowspan="1" colspan="1">13.6 (8.3)</td><td align="center" rowspan="1" colspan="1">0.174</td><td align="center" rowspan="1" colspan="1">15.9 (9.1)</td><td align="center" rowspan="1" colspan="1">16.5 (11.9)</td><td align="center" rowspan="1" colspan="1">0.025</td></tr><tr><td align="left" rowspan="1" colspan="1">Sit and reach (cm)</td><td align="center" rowspan="1" colspan="1">14.9 (6.2)</td><td align="center" rowspan="1" colspan="1">13.6 (6.2)</td><td align="center" rowspan="1" colspan="1">0.304</td><td align="center" rowspan="1" colspan="1">10.2 (8.4)</td><td align="center" rowspan="1" colspan="1">12.7 (7.4)</td><td align="center" rowspan="1" colspan="1">0.010</td></tr><tr><td align="left" rowspan="1" colspan="1">Standing long jump (cm)</td><td align="center" rowspan="1" colspan="1">126.5 (21.2)</td><td align="center" rowspan="1" colspan="1">127.0 (21.7)</td><td align="center" rowspan="1" colspan="1">0.056</td><td align="center" rowspan="1" colspan="1">114.5 (20.3)</td><td align="center" rowspan="1" colspan="1">110.7 (13.3)</td><td align="center" rowspan="1" colspan="1">0.355</td></tr><tr><td align="left" rowspan="1" colspan="1">10 meter shuttle run (sec)</td><td align="center" rowspan="1" colspan="1">16.3 (4.2)</td><td align="center" rowspan="1" colspan="1">16.8 (2.7)</td><td align="center" rowspan="1" colspan="1">0.062</td><td align="center" rowspan="1" colspan="1">15.2 (0.9)</td><td align="center" rowspan="1" colspan="1">16.4 (4.6)</td><td align="center" rowspan="1" colspan="1">0.216</td></tr><tr><td align="left" rowspan="1" colspan="1">20 meter pacer (n)</td><td align="center" rowspan="1" colspan="1">13.2 (5.8)</td><td align="center" rowspan="1" colspan="1">10.9 (5.9)</td><td align="center" rowspan="1" colspan="1">0.843</td><td align="center" rowspan="1" colspan="1">10.5 (6.3)</td><td align="center" rowspan="1" colspan="1">12.1 (4.7)</td><td align="center" rowspan="1" colspan="1">0.108</td></tr><tr><td align="left" colspan="7" rowspan="1">Blood variables</td></tr><tr><td align="left" rowspan="1" colspan="1">Insulin (<italic>u</italic>IU)</td><td align="center" rowspan="1" colspan="1">10.4 (7.5)</td><td align="center" rowspan="1" colspan="1">11.2 (9.5)</td><td align="center" rowspan="1" colspan="1">0.734</td><td align="center" rowspan="1" colspan="1">11.2 (6.1)</td><td align="center" rowspan="1" colspan="1">7.6 (3.0)</td><td align="center" rowspan="1" colspan="1">0.018</td></tr><tr><td align="left" rowspan="1" colspan="1">hs-CRP (mg/mL)</td><td align="center" rowspan="1" colspan="1">1.60 (2.89)</td><td align="center" rowspan="1" colspan="1">1.43 (1.53)</td><td align="center" rowspan="1" colspan="1">0.431</td><td align="center" rowspan="1" colspan="1">1.18 (1.37)</td><td align="center" rowspan="1" colspan="1">0.71 (0.68)</td><td align="center" rowspan="1" colspan="1">0.305</td></tr><tr><td align="left" rowspan="1" colspan="1">Leptin (ng/mL)<sup>a</sup></td><td align="center" rowspan="1" colspan="1">10.9 (7.2)</td><td align="center" rowspan="1" colspan="1">12.5 (12.6)</td><td align="center" rowspan="1" colspan="1">0.377</td><td align="center" rowspan="1" colspan="1">18.7 (16.1)</td><td align="center" rowspan="1" colspan="1">14.9 (15.5)</td><td align="center" rowspan="1" colspan="1">0.022</td></tr><tr><td align="left" rowspan="1" colspan="1">Adiponectin (μg/mL)<sup>a</sup></td><td align="center" rowspan="1" colspan="1">6.45 (3.75)</td><td align="center" rowspan="1" colspan="1">6.37 (3.87)</td><td align="center" rowspan="1" colspan="1">0.507</td><td align="center" rowspan="1" colspan="1">7.46 (2.77)</td><td align="center" rowspan="1" colspan="1">7.92 (3.14)</td><td align="center" rowspan="1" colspan="1">0.248</td></tr><tr><td align="left" rowspan="1" colspan="1">Leptin/adiponectin ratio<sup>a</sup></td><td align="center" rowspan="1" colspan="1">2.87 (3.02)</td><td align="center" rowspan="1" colspan="1">3.66 (4.82)</td><td align="center" rowspan="1" colspan="1">0.220</td><td align="center" rowspan="1" colspan="1">3.16 (3.40)</td><td align="center" rowspan="1" colspan="1">2.20 (2.04)</td><td align="center" rowspan="1" colspan="1">0.013</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>Data are presented as the mean (standard deviation). <italic>p</italic>-values were obtained by paired <italic>t</italic>-test or <sup>a</sup>Wilcoxon signed-rank test.</p></fn></table-wrap-foot></table-wrap><p>We measured the changes in serological biomarkers related to metabolic status following 12 weeks of exercise in breast cancer survivors. Fasting insulin level was significantly decreased by 32% after exercise training (<italic>p</italic> = 0.018), whereas the change in high-sensitivity C-reactive protein level was not significant (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>). As an obesity-related adipokine, the serum level of leptin was decreased by exercise training (<italic>p</italic> = 0.022), whereas leptin levels remained unchanged in the control group. The leptin-to-adiponectin ratio, a preferential index of cardiometabolic diseases, was significantly reduced by exercise training (<italic>p</italic> = 0.013), although the adiponectin level remained unchanged (<xref ref-type="table" rid="pone.0171771.t002">Table 2</xref>).</p><p>We performed an enzyme linked immune sorbent assay to measure the serum levels of DKK1 and SFRP1, which are negative modulators of the Wnt signaling pathway. As shown in <xref ref-type="fig" rid="pone.0171771.g002">Fig 2</xref>, exercise training elicited noteworthy reductions in DKK1 (baseline vs. after 12 weeks, mean ± SEM, 2571 ± 151 vs. 1716 ± 145 pg/ml, <italic>p</italic> = 0.002) and SFRP1 (880 ± 119 vs. 468 ± 75 pg/ml, <italic>p</italic> = 0.008) levels in the serum of breast cancer survivors, whereas no changes were detected in the control group (DKK1: 2613 ± 203 vs. 2365 ± 197 pg/ml, <italic>p</italic> = 0.08; SFRP1: 1,085 ± 149 vs. 1,039 ± 110 pg/ml, <italic>p</italic> = 0.35). Additionally, we measured serum level of DKK1 in twenty-one healthy volunteers. We observed that basal DKK1 levels of the age-matched healthy women were significantly lower than those of breast cancer survivors (healthy women vs. breast cancer survivors, 1831 ± 161 vs. 2594 ± 128 pg/ml, <italic>p</italic> < 0.001). However, exercise did not affect the serum level of DKK1 in the healthy women.</p><fig id="pone.0171771.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0171771.g002</object-id><label>Fig 2</label><caption><title>Changes in circulating levels of Dickkpof-1 (DKK1) and secreted frizzled-related protein-1 (SFRP1) elicited by 12-weeks of exercise training in breast cancer survivors.</title><p>**<italic>p</italic> < 0.01 according to Wilcoxon signed-rank test.</p></caption><graphic xlink:href="pone.0171771.g002"></graphic></fig></sec><sec sec-type="conclusions" id="sec020"><title>Discussion</title><p>Exercise, especially combined aerobic-resistance exercise regimen, not only improves body composition and cardio-respiratory fitness, but also enhances musculoskeletal strength and range of motion of the shoulder in breast cancer survivors [<xref rid="pone.0171771.ref030" ref-type="bibr">30</xref>–<xref rid="pone.0171771.ref032" ref-type="bibr">32</xref>]. We adopted a combined exercise regimen to test whether the beneficial effects of exercise training occur in Wnt signaling-related biomarkers as well. In this study, we evaluated the effects of long-term exercise training on parameters related to physical fitness and serological markers in survivors of breast cancer. Exercise training for 12 weeks successfully improved muscle strength, endurance, and flexibility. Body fat was reduced and insulin sensitivity was enhanced by the exercise program. We analyzed the changes in arm circumference as a functional characteristic. Patients and survivors of breast cancer present declines in physical performance and edema of the shoulder and arm. Additionally, they have insufficient functional shoulder range of motion after surgery [<xref rid="pone.0171771.ref033" ref-type="bibr">33</xref>]. It has been indicated that various exercises enhance shoulder movement and arm edema [<xref rid="pone.0171771.ref034" ref-type="bibr">34</xref>]. Our study showed that arm circumferences were significantly decreased in the exercised group, which may contribute to improved functional movements in survivors of breast cancer.</p><p>These beneficial effects of exercise were accompanied by reduced serum levels of the Wnt signaling modulators DKK1 and SFRP1. Over the past 20 years, various regulatory factors in Wnt signaling have been suggested and the impacts of their serum levels have been investigated. DKK1 was proposed as an independent prognostic biomarker of relapse-free survival in patients with breast cancer [<xref rid="pone.0171771.ref016" ref-type="bibr">16</xref>]. A previous study demonstrated that the serum level of DKK1 in breast cancer was correlated with tumor grade and lymph node metastasis. Furthermore, circulating DKK1 level is consistently increased during bone metastases in patients with breast cancer [<xref rid="pone.0171771.ref022" ref-type="bibr">22</xref>]. Hence, regulating DKK1 function or expression was suggested as an important therapeutic target in tumor-induced bone resorption and multiple myeloma [<xref rid="pone.0171771.ref035" ref-type="bibr">35</xref>,<xref rid="pone.0171771.ref036" ref-type="bibr">36</xref>].</p><p>Currently, the mechanism for regulation of tumor progression by Wnt inhibitors is not clearly understood. However, it has been suggested that downregulation or deletion of β-catenin in myeloid-derived cells induces immunosuppression and tumor cell growth [<xref rid="pone.0171771.ref037" ref-type="bibr">37</xref>]. Increased serum level of DKK1, an inhibitor of the Wnt-β-catenin pathway, has been reported in pancreatic, gastric, hepatic, lung, esophagus, and breast cancer patient [<xref rid="pone.0171771.ref038" ref-type="bibr">38</xref>]. Furthermore, high circulating DKK1 levels correlate with poor prognosis in various cancers [<xref rid="pone.0171771.ref039" ref-type="bibr">39</xref>]. D’Amico et al. reported that percentage of CD4+ and CD8+ T cells are increased in anti-DKK1 treated mice. The authors showed that anti-DKK1 treatment increased β-catenin expression in myeloid-derived suppressor cells and suggested that attenuating DKK1 activity by neutralization recruited T cells to the tumor site and decreased tumor growth [<xref rid="pone.0171771.ref025" ref-type="bibr">25</xref>]. These results support our hypothesis that reduction of DKK1 could contribute to the combat against cancer progression.</p><p>To date, only two studies have shown an effect of exercise on the expression levels of DKK1. In a study on humans, reduced serum level of DKK1 was detected 3 days after the subject completed an ultra-marathon (246 km) compared to pre- and immediate post-race levels of DKK1 in healthy individuals [<xref rid="pone.0171771.ref026" ref-type="bibr">26</xref>]. In an experimental animal study, sedentary rats showed higher expression levels of DKK1 compared to controls [<xref rid="pone.0171771.ref027" ref-type="bibr">27</xref>]. Wnt expression is also increased in exercised human subjects and animal models [<xref rid="pone.0171771.ref040" ref-type="bibr">40</xref>,<xref rid="pone.0171771.ref041" ref-type="bibr">41</xref>]. In addition, it has been reported that increased Wnt proteins regulate effector T‑cell development, regulatory T‑cell activation and dendritic-cell maturation [<xref rid="pone.0171771.ref042" ref-type="bibr">42</xref>]. In addition, Gattinoni et al. suggested that canonical Wnt signaling stimulates proliferation of immature T and B cells [<xref rid="pone.0171771.ref043" ref-type="bibr">43</xref>]. Therefore, activation of Wnt signaling in immune cells by exercise may stimulate cancer immune response leading to tumor suppression. Moreover, Cao Dinh et al. observed that exercise is known to increase CD4+/CD8+ counts and improve immune functions [<xref rid="pone.0171771.ref044" ref-type="bibr">44</xref>]. Our hypothesis suggests that a diminution of Wnt inhibitor by exercise could have immune-stimulatory effects to prevent tumor growth and cancer stage progression.</p><p>This is the first study showing that exercise training leads to decreased serum SFRP1 levels in patients with cancer. Accumulating studies have indicated that aberrant and frequent methylation and silencing of the SFRP1 gene results in activation of the Wnt pathway in breast carcinogenesis. However, the availability of SFRP1 expression as a prognostic marker is highly limited in early stage of cancer, as SFRP1 expression does not reflect the tumor grade or lymph node metastasis status associated with poor prognosis [<xref rid="pone.0171771.ref045" ref-type="bibr">45</xref>–<xref rid="pone.0171771.ref047" ref-type="bibr">47</xref>]. Interestingly, SFRP1 was found to be expressed in mature adipocytes in human adipose tissue and was increased in obese subjects [<xref rid="pone.0171771.ref048" ref-type="bibr">48</xref>]. In addition, SFRP1 may act as a determinant of adipose tissue expandability by participating in the paracrine regulation of human adipogenesis. In this regard, decreased serum SFRP1 by exercise training appears to be attributable to improved body composition, including decreases in body fat percentage and visceral fat areas.</p><p>Breast cancer is closely associated with metabolic syndrome [<xref rid="pone.0171771.ref049" ref-type="bibr">49</xref>,<xref rid="pone.0171771.ref050" ref-type="bibr">50</xref>]. The serum levels of various adipokines, including leptin and adiponectin, have been indicated as biomarkers for insulin resistance and metabolic syndrome [<xref rid="pone.0171771.ref051" ref-type="bibr">51</xref>]. Leptin plays a key role in the control of food intake, metabolism, and energy consumption. However, metabolic stress induces leptin resistance and increases the leptin/adiponectin ratio. To date, accumulating evidence indicates that increased serum levels of leptin and decreased adiponectin are associated with breast cancer risk [<xref rid="pone.0171771.ref050" ref-type="bibr">50</xref>,<xref rid="pone.0171771.ref051" ref-type="bibr">51</xref>]. In contrast, weight loss with exercise decreases the leptin/adiponectin ratio [<xref rid="pone.0171771.ref052" ref-type="bibr">52</xref>,<xref rid="pone.0171771.ref053" ref-type="bibr">53</xref>]. Our results also revealed significant decreases in both the serum level of leptin and leptin/adiponectin ratio. However, other studies indicated that 6-month combined exercise intervention programs did not affect the plasma level of adiponectin, which was similar to our results [<xref rid="pone.0171771.ref033" ref-type="bibr">33</xref>,<xref rid="pone.0171771.ref034" ref-type="bibr">34</xref>]. Increased serum levels of insulin caused by insulin resistance induce proliferative abnormalities, which are likely to cause breast cancer [<xref rid="pone.0171771.ref054" ref-type="bibr">54</xref>]. Moreover, increased insulin levels are associated with greater estrogen production, which can have negative effects on breast cancer. Therefore, reducing the plasma level of insulin through exercise can also have therapeutic effects on survivors of breast cancer.</p><p>Our study had several limitations. First, this was a pilot study. Pilot studies have inherent limitations such as small sample sizes. The small sample size reduced the statistical power in identifying significant changes. In addition, the duration of the exercise intervention program may not be sufficiently long and may have influenced the variables related to pre- and post-exercise intervention.</p></sec><sec sec-type="conclusions" id="sec021"><title>Conclusion</title><p>We demonstrated that long-term exercise decreases the serum levels of DKK1 and SFRP1 and improves physical fitness and biomarker levels related to metabolic conditions in breast cancer survivors. These results indicate the possible involvement of Wnt signaling in the beneficial effects of exercise in patients with cancer. Further studies are required to elucidate the molecular mechanisms of these changes under pathological conditions as well as during interventional periods. These efforts will reveal useful diagnostic/prognostic biomarkers and therapeutic targets related to exercise-induced benefits in patients with cancer.</p></sec><sec sec-type="supplementary-material" id="sec022"><title>Supporting information</title><supplementary-material content-type="local-data" id="pone.0171771.s001"><label>S1 Text</label><caption><title>Study protocol (Original Korean version).</title><p>(DOCX)</p></caption><media xlink:href="pone.0171771.s001.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0171771.s002"><label>S2 Text</label><caption><title>Study protocol (English version).</title><p>(DOCX)</p></caption><media xlink:href="pone.0171771.s002.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0171771.s003"><label>S1 Table</label><caption><title>CONSORT checklist.</title><p>(DOCX)</p></caption><media xlink:href="pone.0171771.s003.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>The authors acknowledge Eun Ju Kim and Miyeol Choi for invaluable help with participant recruitment and data collection.</p></ack><ref-list><title>References</title><ref id="pone.0171771.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Binkley</surname><given-names>JM</given-names></name>, <name><surname>Harris</surname><given-names>SR</given-names></name>, <name><surname>Levangie</surname><given-names>PK</given-names></name>, <name><surname>Pearl</surname><given-names>M</given-names></name>, <name><surname>Guglielmino</surname><given-names>J</given-names></name>, <name><surname>Kraus</surname><given-names>V</given-names></name>, <etal>et al</etal><article-title>Patient perspectives on breast cancer treatment side effects and the prospective surveillance model for physical rehabilitation for women with breast cancer</article-title>. <source>Cancer</source>. <year>2012</year>;<volume>118</volume>: <fpage>2207</fpage>–<lpage>2216</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/cncr.27469">10.1002/cncr.27469</ext-link></comment><pub-id pub-id-type="pmid">22488695</pub-id></mixed-citation></ref><ref id="pone.0171771.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Loprinzi</surname><given-names>PD</given-names></name>, <name><surname>Cardinal</surname><given-names>BJ</given-names></name>. <article-title>Effects of physical activity on common side effects of breast cancer treatment</article-title>. <source>Breast Cancer</source>. <year>2012</year>;<volume>19</volume>: <fpage>4</fpage>–<lpage>10</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s12282-011-0292-3">10.1007/s12282-011-0292-3</ext-link></comment><pub-id pub-id-type="pmid">21725654</pub-id></mixed-citation></ref><ref id="pone.0171771.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>Knols</surname><given-names>R</given-names></name>, <name><surname>Aaronson</surname><given-names>NK</given-names></name>, <name><surname>Uebelhart</surname><given-names>D</given-names></name>, <name><surname>Fransen</surname><given-names>J</given-names></name>, <name><surname>Aufdemkampe</surname><given-names>G</given-names></name>. <article-title>Physical exercise in cancer patients during and after medical treatment: a systematic review of randomized and controlled clinical trials</article-title>. <source>J Clin Oncol</source>. <year>2005</year>;<volume>23</volume>: <fpage>3830</fpage>–<lpage>3842</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1200/JCO.2005.02.148">10.1200/JCO.2005.02.148</ext-link></comment><pub-id pub-id-type="pmid">15923576</pub-id></mixed-citation></ref><ref id="pone.0171771.ref004"><label>4</label><mixed-citation publication-type="journal"><name><surname>McNeely</surname><given-names>ML</given-names></name>, <name><surname>Campbell</surname><given-names>KL</given-names></name>, <name><surname>Rowe</surname><given-names>BH</given-names></name>, <name><surname>Klassen</surname><given-names>TP</given-names></name>, <name><surname>Mackey</surname><given-names>JR</given-names></name>, <name><surname>Courneya</surname><given-names>KS</given-names></name>. <article-title>Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis</article-title>. <source>CMAJ</source>. <year>2006</year>;<volume>175</volume>: <fpage>34</fpage>–<lpage>41</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1503/cmaj.051073">10.1503/cmaj.051073</ext-link></comment><pub-id pub-id-type="pmid">16818906</pub-id></mixed-citation></ref><ref id="pone.0171771.ref005"><label>5</label><mixed-citation publication-type="journal"><name><surname>Polakis</surname><given-names>P</given-names></name>. <article-title>Wnt signaling in cancer</article-title>. <source>Cold Spring Harb Perspect Biol</source>. <year>2012</year>;<volume>4</volume>:</mixed-citation></ref><ref id="pone.0171771.ref006"><label>6</label><mixed-citation publication-type="journal"><name><surname>Anastas</surname><given-names>JN</given-names></name>, <name><surname>Moon</surname><given-names>RT</given-names></name>. <article-title>WNT signalling pathways as therapeutic targets in cancer</article-title>. <source>Nat Rev Cancer</source>. <year>2013</year>;<volume>13</volume>: <fpage>11</fpage>–<lpage>26</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/nrc3419">10.1038/nrc3419</ext-link></comment><pub-id pub-id-type="pmid">23258168</pub-id></mixed-citation></ref><ref id="pone.0171771.ref007"><label>7</label><mixed-citation publication-type="journal"><name><surname>Brennan</surname><given-names>KR</given-names></name>, <name><surname>Brown</surname><given-names>AM</given-names></name>. <article-title>Wnt proteins in mammary development and cancer</article-title>. <source>J Mammary Gland Biol Neoplasia</source>. <year>2004</year>;<volume>9</volume>: <fpage>119</fpage>–<lpage>131</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1023/B:JOMG.0000037157.94207.33">10.1023/B:JOMG.0000037157.94207.33</ext-link></comment><pub-id pub-id-type="pmid">15300008</pub-id></mixed-citation></ref><ref id="pone.0171771.ref008"><label>8</label><mixed-citation publication-type="journal"><name><surname>Schlange</surname><given-names>T</given-names></name>, <name><surname>Matsuda</surname><given-names>Y</given-names></name>, <name><surname>Lienhard</surname><given-names>S</given-names></name>, <name><surname>Huber</surname><given-names>A</given-names></name>, <name><surname>Hynes</surname><given-names>NE</given-names></name>. <article-title>Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation</article-title>. <source>Breast Cancer Res</source>. <year>2007</year>;<volume>9</volume>: <fpage>R63</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/bcr1769">10.1186/bcr1769</ext-link></comment><pub-id pub-id-type="pmid">17897439</pub-id></mixed-citation></ref><ref id="pone.0171771.ref009"><label>9</label><mixed-citation publication-type="journal"><name><surname>Surana</surname><given-names>R</given-names></name>, <name><surname>Sikka</surname><given-names>S</given-names></name>, <name><surname>Cai</surname><given-names>W</given-names></name>, <name><surname>Shin</surname><given-names>EM</given-names></name>, <name><surname>Warrier</surname><given-names>SR</given-names></name>, <name><surname>Tan</surname><given-names>HJ</given-names></name>, <etal>et al</etal><article-title>Secreted frizzled related proteins: Implications in cancers</article-title>. <source>Biochim Biophys Acta</source>. <year>2014</year>;<volume>1845</volume>: <fpage>53</fpage>–<lpage>65</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.bbcan.2013.11.004">10.1016/j.bbcan.2013.11.004</ext-link></comment><pub-id pub-id-type="pmid">24316024</pub-id></mixed-citation></ref><ref id="pone.0171771.ref010"><label>10</label><mixed-citation publication-type="journal"><name><surname>Baron</surname><given-names>R</given-names></name>, <name><surname>Kneissel</surname><given-names>M</given-names></name>. <article-title>WNT signaling in bone homeostasis and disease: from human mutations to treatments</article-title>. <source>Nat Med</source>. <year>2013</year>;<volume>19</volume>: <fpage>179</fpage>–<lpage>192</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/nm.3074">10.1038/nm.3074</ext-link></comment><pub-id pub-id-type="pmid">23389618</pub-id></mixed-citation></ref><ref id="pone.0171771.ref011"><label>11</label><mixed-citation publication-type="journal"><name><surname>Gough</surname><given-names>NR</given-names></name>. <article-title>Focus issue: Wnt and beta-catenin signaling in development and disease</article-title>. <source>Sci Signal</source>. <year>2012</year>;<volume>5</volume>: <fpage>eg2</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1126/scisignal.2002806">10.1126/scisignal.2002806</ext-link></comment><pub-id pub-id-type="pmid">22234609</pub-id></mixed-citation></ref><ref id="pone.0171771.ref012"><label>12</label><mixed-citation publication-type="journal"><name><surname>Niehrs</surname><given-names>C</given-names></name>. <article-title>Function and biological roles of the Dickkopf family of Wnt modulators</article-title>. <source>Oncogene</source>. <year>2006</year>;<volume>25</volume>: <fpage>7469</fpage>–<lpage>7481</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.onc.1210054">10.1038/sj.onc.1210054</ext-link></comment><pub-id pub-id-type="pmid">17143291</pub-id></mixed-citation></ref><ref id="pone.0171771.ref013"><label>13</label><mixed-citation publication-type="journal"><name><surname>Niehrs</surname><given-names>C</given-names></name>. <article-title>The complex world of WNT receptor signalling</article-title>. <source>Nat Rev Mol Cell Biol</source>. <year>2012</year>;<volume>13</volume>: <fpage>767</fpage>–<lpage>779</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/nrm3470">10.1038/nrm3470</ext-link></comment><pub-id pub-id-type="pmid">23151663</pub-id></mixed-citation></ref><ref id="pone.0171771.ref014"><label>14</label><mixed-citation publication-type="journal"><name><surname>Sheldahl</surname><given-names>LC</given-names></name>, <name><surname>Park</surname><given-names>M</given-names></name>, <name><surname>Malbon</surname><given-names>CC</given-names></name>, <name><surname>Moon</surname><given-names>RT</given-names></name>. <article-title>Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner</article-title>. <source>Curr Biol</source>. <year>1999</year>;<volume>9</volume>: <fpage>695</fpage>–<lpage>698</lpage>. <pub-id pub-id-type="pmid">10395542</pub-id></mixed-citation></ref><ref id="pone.0171771.ref015"><label>15</label><mixed-citation publication-type="journal"><name><surname>Kuhl</surname><given-names>M</given-names></name>, <name><surname>Sheldahl</surname><given-names>LC</given-names></name>, <name><surname>Malbon</surname><given-names>CC</given-names></name>, <name><surname>Moon</surname><given-names>RT</given-names></name>. <article-title>Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus</article-title>. <source>J Biol Chem</source>. <year>2000</year>;<volume>275</volume>: <fpage>12701</fpage>–<lpage>12711</lpage>. <pub-id pub-id-type="pmid">10777564</pub-id></mixed-citation></ref><ref id="pone.0171771.ref016"><label>16</label><mixed-citation publication-type="journal"><name><surname>Zhou</surname><given-names>SJ</given-names></name>, <name><surname>Zhuo</surname><given-names>SR</given-names></name>, <name><surname>Yang</surname><given-names>XQ</given-names></name>, <name><surname>Qin</surname><given-names>CX</given-names></name>, <name><surname>Wang</surname><given-names>ZL</given-names></name>. <article-title>Serum Dickkopf-1 expression level positively correlates with a poor prognosis in breast cancer</article-title>. <source>Diagn Pathol</source>. <year>2014</year>;<volume>9</volume>: <fpage>161</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/s13000-014-0161-4">10.1186/s13000-014-0161-4</ext-link></comment><pub-id pub-id-type="pmid">25116444</pub-id></mixed-citation></ref><ref id="pone.0171771.ref017"><label>17</label><mixed-citation publication-type="journal"><name><surname>Rachner</surname><given-names>TD</given-names></name>, <name><surname>Gobel</surname><given-names>A</given-names></name>, <name><surname>Benad-Mehner</surname><given-names>P</given-names></name>, <name><surname>Hofbauer</surname><given-names>LC</given-names></name>, <name><surname>Rauner</surname><given-names>M</given-names></name>. <article-title>Dickkopf-1 as a mediator and novel target in malignant bone disease</article-title>. <source>Cancer Lett</source>. <year>2014</year>;<volume>346</volume>: <fpage>172</fpage>–<lpage>177</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.canlet.2014.01.010">10.1016/j.canlet.2014.01.010</ext-link></comment><pub-id pub-id-type="pmid">24462802</pub-id></mixed-citation></ref><ref id="pone.0171771.ref018"><label>18</label><mixed-citation publication-type="journal"><name><surname>Niida</surname><given-names>A</given-names></name>, <name><surname>Hiroko</surname><given-names>T</given-names></name>, <name><surname>Kasai</surname><given-names>M</given-names></name>, <name><surname>Furukawa</surname><given-names>Y</given-names></name>, <name><surname>Nakamura</surname><given-names>Y</given-names></name>, <name><surname>Suzuki</surname><given-names>Y</given-names></name>, <etal>et al</etal><article-title>DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway</article-title>. <source>Oncogene</source>. <year>2004</year>;<volume>23</volume>: <fpage>8520</fpage>–<lpage>8526</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.onc.1207892">10.1038/sj.onc.1207892</ext-link></comment><pub-id pub-id-type="pmid">15378020</pub-id></mixed-citation></ref><ref id="pone.0171771.ref019"><label>19</label><mixed-citation publication-type="journal"><name><surname>Kawano</surname><given-names>Y</given-names></name>, <name><surname>Kypta</surname><given-names>R</given-names></name>. <article-title>Secreted antagonists of the Wnt signalling pathway</article-title>. <source>J Cell Sci</source>. <year>2003</year>;<volume>116</volume>: <fpage>2627</fpage>–<lpage>2634</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1242/jcs.00623">10.1242/jcs.00623</ext-link></comment><pub-id pub-id-type="pmid">12775774</pub-id></mixed-citation></ref><ref id="pone.0171771.ref020"><label>20</label><mixed-citation publication-type="journal"><name><surname>Bernemann</surname><given-names>C</given-names></name>, <name><surname>Hulsewig</surname><given-names>C</given-names></name>, <name><surname>Ruckert</surname><given-names>C</given-names></name>, <name><surname>Schafer</surname><given-names>S</given-names></name>, <name><surname>Blumel</surname><given-names>L</given-names></name>, <name><surname>Hempel</surname><given-names>G</given-names></name>, <etal>et al</etal><article-title>Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling</article-title>. <source>Mol Cancer</source>. <year>2014</year>;<volume>13</volume>: <fpage>174</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/1476-4598-13-174">10.1186/1476-4598-13-174</ext-link></comment><pub-id pub-id-type="pmid">25033833</pub-id></mixed-citation></ref><ref id="pone.0171771.ref021"><label>21</label><mixed-citation publication-type="journal"><name><surname>Voorzanger-Rousselot</surname><given-names>N</given-names></name>, <name><surname>Goehrig</surname><given-names>D</given-names></name>, <name><surname>Journe</surname><given-names>F</given-names></name>, <name><surname>Doriath</surname><given-names>V</given-names></name>, <name><surname>Body</surname><given-names>JJ</given-names></name>, <name><surname>Clezardin</surname><given-names>P</given-names></name>, <etal>et al</etal><article-title>Increased Dickkopf-1 expression in breast cancer bone metastases</article-title>. <source>Br J Cancer</source>. <year>2007</year>;<volume>97</volume>: <fpage>964</fpage>–<lpage>970</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.bjc.6603959">10.1038/sj.bjc.6603959</ext-link></comment><pub-id pub-id-type="pmid">17876334</pub-id></mixed-citation></ref><ref id="pone.0171771.ref022"><label>22</label><mixed-citation publication-type="journal"><name><surname>Voorzanger-Rousselot</surname><given-names>N</given-names></name>, <name><surname>Journe</surname><given-names>F</given-names></name>, <name><surname>Doriath</surname><given-names>V</given-names></name>, <name><surname>Body</surname><given-names>JJ</given-names></name>, <name><surname>Garnero</surname><given-names>P</given-names></name>. <article-title>Assessment of circulating Dickkopf-1 with a new two-site immunoassay in healthy subjects and women with breast cancer and bone metastases</article-title>. <source>Calcif Tissue Int</source>. <year>2009</year>;<volume>84</volume>: <fpage>348</fpage>–<lpage>354</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s00223-009-9225-y">10.1007/s00223-009-9225-y</ext-link></comment><pub-id pub-id-type="pmid">19252761</pub-id></mixed-citation></ref><ref id="pone.0171771.ref023"><label>23</label><mixed-citation publication-type="journal"><name><surname>Han</surname><given-names>SX</given-names></name>, <name><surname>Zhou</surname><given-names>X</given-names></name>, <name><surname>Sui</surname><given-names>X</given-names></name>, <name><surname>He</surname><given-names>CC</given-names></name>, <name><surname>Cai</surname><given-names>MJ</given-names></name>, <name><surname>Ma</surname><given-names>JL</given-names></name>, <etal>et al</etal><article-title>Serum dickkopf-1 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer</article-title>. <source>Oncotarget</source>. <year>2015</year>;<volume>6</volume>: <fpage>19907</fpage>–<lpage>19917</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.18632/oncotarget.4529">10.18632/oncotarget.4529</ext-link></comment><pub-id pub-id-type="pmid">26101916</pub-id></mixed-citation></ref><ref id="pone.0171771.ref024"><label>24</label><mixed-citation publication-type="journal"><name><surname>Rachner</surname><given-names>TD</given-names></name>, <name><surname>Thiele</surname><given-names>S</given-names></name>, <name><surname>Gobel</surname><given-names>A</given-names></name>, <name><surname>Browne</surname><given-names>A</given-names></name>, <name><surname>Fuessel</surname><given-names>S</given-names></name>, <name><surname>Erdmann</surname><given-names>K</given-names></name>, <etal>et al</etal><article-title>High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients</article-title>. <source>BMC Cancer</source>. <year>2014</year>;<volume>14</volume>: <fpage>649</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/1471-2407-14-649">10.1186/1471-2407-14-649</ext-link></comment><pub-id pub-id-type="pmid">25182503</pub-id></mixed-citation></ref><ref id="pone.0171771.ref025"><label>25</label><mixed-citation publication-type="journal"><name><surname>D'Amico</surname><given-names>L</given-names></name>, <name><surname>Mahajan</surname><given-names>S</given-names></name>, <name><surname>Capietto</surname><given-names>AH</given-names></name>, <name><surname>Yang</surname><given-names>Z</given-names></name>, <name><surname>Zamani</surname><given-names>A</given-names></name>, <name><surname>Ricci</surname><given-names>B</given-names></name>, <etal>et al</etal><article-title>Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer</article-title>. <source>J Exp Med</source>. <year>2016</year>;<volume>213</volume>: <fpage>827</fpage>–<lpage>840</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1084/jem.20150950">10.1084/jem.20150950</ext-link></comment><pub-id pub-id-type="pmid">27045006</pub-id></mixed-citation></ref><ref id="pone.0171771.ref026"><label>26</label><mixed-citation publication-type="journal"><name><surname>Kerschan-Schindl</surname><given-names>K</given-names></name>, <name><surname>Thalmann</surname><given-names>MM</given-names></name>, <name><surname>Weiss</surname><given-names>E</given-names></name>, <name><surname>Tsironi</surname><given-names>M</given-names></name>, <name><surname>Foger-Samwald</surname><given-names>U</given-names></name>, <name><surname>Meinhart</surname><given-names>J</given-names></name>, <etal>et al</etal><article-title>Changes in serum levels of myokines and Wnt-antagonists after an ultramarathon race</article-title>. <source>PLoS One</source>. <year>2015</year>;<volume>10</volume>: <fpage>e0132478</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1371/journal.pone.0132478">10.1371/journal.pone.0132478</ext-link></comment><pub-id pub-id-type="pmid">26147574</pub-id></mixed-citation></ref><ref id="pone.0171771.ref027"><label>27</label><mixed-citation publication-type="journal"><name><surname>Bayod</surname><given-names>S</given-names></name>, <name><surname>Mennella</surname><given-names>I</given-names></name>, <name><surname>Sanchez-Roige</surname><given-names>S</given-names></name>, <name><surname>Lalanza</surname><given-names>JF</given-names></name>, <name><surname>Escorihuela</surname><given-names>RM</given-names></name>, <name><surname>Camins</surname><given-names>A</given-names></name>, <etal>et al</etal><article-title>Wnt pathway regulation by long-term moderate exercise in rat hippocampus</article-title>. <source>Brain Res</source>. <year>2014</year>;<volume>1543</volume>: <fpage>38</fpage>–<lpage>48</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.brainres.2013.10.048">10.1016/j.brainres.2013.10.048</ext-link></comment><pub-id pub-id-type="pmid">24183784</pub-id></mixed-citation></ref><ref id="pone.0171771.ref028"><label>28</label><mixed-citation publication-type="book"><name><surname>Irwin</surname><given-names>ML</given-names></name>, <collab>American College of Sports Medicine</collab>. <source>ACSM's guide to exercise and cancer survivorship</source>. <publisher-loc>Champaign, IL</publisher-loc>: <publisher-name>Human Kinetics</publisher-name>; <year>2012</year>.</mixed-citation></ref><ref id="pone.0171771.ref029"><label>29</label><mixed-citation publication-type="journal"><name><surname>Borg</surname><given-names>GA</given-names></name>. <article-title>Psychophysical bases of perceived exertion</article-title>. <source>Med Sci Sports Exerc</source>. <year>1982</year>;<volume>14</volume>: <fpage>377</fpage>–<lpage>381</lpage>. <pub-id pub-id-type="pmid">7154893</pub-id></mixed-citation></ref><ref id="pone.0171771.ref030"><label>30</label><mixed-citation publication-type="journal"><name><surname>Fairey</surname><given-names>AS</given-names></name>, <name><surname>Courneya</surname><given-names>KS</given-names></name>, <name><surname>Field</surname><given-names>CJ</given-names></name>, <name><surname>Bell</surname><given-names>GJ</given-names></name>, <name><surname>Jones</surname><given-names>LW</given-names></name>, <name><surname>Martin</surname><given-names>BS</given-names></name>, <etal>et al</etal><article-title>Effect of exercise training on C-reactive protein in postmenopausal breast cancer survivors: a randomized controlled trial</article-title>. <source>Brain Behav Immun</source>. <year>2005</year>;<volume>19</volume>: <fpage>381</fpage>–<lpage>388</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.bbi.2005.04.001">10.1016/j.bbi.2005.04.001</ext-link></comment><pub-id pub-id-type="pmid">15922556</pub-id></mixed-citation></ref><ref id="pone.0171771.ref031"><label>31</label><mixed-citation publication-type="journal"><name><surname>Winters-Stone</surname><given-names>KM</given-names></name>, <name><surname>Dobek</surname><given-names>J</given-names></name>, <name><surname>Bennett</surname><given-names>JA</given-names></name>, <name><surname>Nail</surname><given-names>LM</given-names></name>, <name><surname>Leo</surname><given-names>MC</given-names></name>, <name><surname>Schwartz</surname><given-names>A</given-names></name>. <article-title>The effect of resistance training on muscle strength and physical function in older, postmenopausal breast cancer survivors: a randomized controlled trial</article-title>. <source>J Cancer Surviv</source>. <year>2012</year>;<volume>6</volume>: <fpage>189</fpage>–<lpage>199</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s11764-011-0210-x">10.1007/s11764-011-0210-x</ext-link></comment><pub-id pub-id-type="pmid">22193780</pub-id></mixed-citation></ref><ref id="pone.0171771.ref032"><label>32</label><mixed-citation publication-type="journal"><name><surname>Chan</surname><given-names>DN</given-names></name>, <name><surname>Lui</surname><given-names>LY</given-names></name>, <name><surname>So</surname><given-names>WK</given-names></name>. <article-title>Effectiveness of exercise programmes on shoulder mobility and lymphoedema after axillary lymph node dissection for breast cancer: systematic review</article-title>. <source>J Adv Nurs</source>. <year>2010</year>;<volume>66</volume>: <fpage>1902</fpage>–<lpage>1914</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1111/j.1365-2648.2010.05374.x">10.1111/j.1365-2648.2010.05374.x</ext-link></comment><pub-id pub-id-type="pmid">20626480</pub-id></mixed-citation></ref><ref id="pone.0171771.ref033"><label>33</label><mixed-citation publication-type="journal"><name><surname>Riesco</surname><given-names>E</given-names></name>, <name><surname>Choquette</surname><given-names>S</given-names></name>, <name><surname>Audet</surname><given-names>M</given-names></name>, <name><surname>Lebon</surname><given-names>J</given-names></name>, <name><surname>Tessier</surname><given-names>D</given-names></name>, <name><surname>Dionne</surname><given-names>IJ</given-names></name>. <article-title>Effect of exercise training combined with phytoestrogens on adipokines and C-reactive protein in postmenopausal women: a randomized trial</article-title>. <source>Metabolism</source>. <year>2012</year>;<volume>61</volume>: <fpage>273</fpage>–<lpage>280</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.metabol.2011.06.025">10.1016/j.metabol.2011.06.025</ext-link></comment><pub-id pub-id-type="pmid">21864865</pub-id></mixed-citation></ref><ref id="pone.0171771.ref034"><label>34</label><mixed-citation publication-type="journal"><name><surname>Ryan</surname><given-names>AS</given-names></name>, <name><surname>Nicklas</surname><given-names>BJ</given-names></name>, <name><surname>Berman</surname><given-names>DM</given-names></name>, <name><surname>Elahi</surname><given-names>D</given-names></name>. <article-title>Adiponectin levels do not change with moderate dietary induced weight loss and exercise in obese postmenopausal women</article-title>. <source>Int J Obes Relat Metab Disord</source>. <year>2003</year>;<volume>27</volume>: <fpage>1066</fpage>–<lpage>1071</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.ijo.0802387">10.1038/sj.ijo.0802387</ext-link></comment><pub-id pub-id-type="pmid">12917712</pub-id></mixed-citation></ref><ref id="pone.0171771.ref035"><label>35</label><mixed-citation publication-type="journal"><name><surname>Yaccoby</surname><given-names>S</given-names></name>, <name><surname>Ling</surname><given-names>W</given-names></name>, <name><surname>Zhan</surname><given-names>F</given-names></name>, <name><surname>Walker</surname><given-names>R</given-names></name>, <name><surname>Barlogie</surname><given-names>B</given-names></name>, <name><surname>Shaughnessy</surname><given-names>JD</given-names><suffix>Jr.</suffix></name><article-title>Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo</article-title>. <source>Blood</source>. <year>2007</year>;<volume>109</volume>: <fpage>2106</fpage>–<lpage>2111</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1182/blood-2006-09-047712">10.1182/blood-2006-09-047712</ext-link></comment><pub-id pub-id-type="pmid">17068150</pub-id></mixed-citation></ref><ref id="pone.0171771.ref036"><label>36</label><mixed-citation publication-type="journal"><name><surname>Zhou</surname><given-names>F</given-names></name>, <name><surname>Meng</surname><given-names>S</given-names></name>, <name><surname>Song</surname><given-names>H</given-names></name>, <name><surname>Claret</surname><given-names>FX</given-names></name>. <article-title>Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention</article-title>. <source>Blood Rev</source>. <year>2013</year>;<volume>27</volume>: <fpage>261</fpage>–<lpage>267</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.blre.2013.08.002">10.1016/j.blre.2013.08.002</ext-link></comment><pub-id pub-id-type="pmid">24054128</pub-id></mixed-citation></ref><ref id="pone.0171771.ref037"><label>37</label><mixed-citation publication-type="journal"><name><surname>Capietto</surname><given-names>AH</given-names></name>, <name><surname>Kim</surname><given-names>S</given-names></name>, <name><surname>Sanford</surname><given-names>DE</given-names></name>, <name><surname>Linehan</surname><given-names>DC</given-names></name>, <name><surname>Hikida</surname><given-names>M</given-names></name>, <name><surname>Kumosaki</surname><given-names>T</given-names></name>, <etal>et al</etal><article-title>Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer</article-title>. <source>J Exp Med</source>. <year>2013</year>;<volume>210</volume>: <fpage>2257</fpage>–<lpage>2271</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1084/jem.20130281">10.1084/jem.20130281</ext-link></comment><pub-id pub-id-type="pmid">24127488</pub-id></mixed-citation></ref><ref id="pone.0171771.ref038"><label>38</label><mixed-citation publication-type="journal"><name><surname>Yamabuki</surname><given-names>T</given-names></name>, <name><surname>Takano</surname><given-names>A</given-names></name>, <name><surname>Hayama</surname><given-names>S</given-names></name>, <name><surname>Ishikawa</surname><given-names>N</given-names></name>, <name><surname>Kato</surname><given-names>T</given-names></name>, <name><surname>Miyamoto</surname><given-names>M</given-names></name>, <etal>et al</etal><article-title>Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas</article-title>. <source>Cancer Res</source>. <year>2007</year>;<volume>67</volume>: <fpage>2517</fpage>–<lpage>2525</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1158/0008-5472.CAN-06-3369">10.1158/0008-5472.CAN-06-3369</ext-link></comment><pub-id pub-id-type="pmid">17363569</pub-id></mixed-citation></ref><ref id="pone.0171771.ref039"><label>39</label><mixed-citation publication-type="journal"><name><surname>Liu</surname><given-names>Y</given-names></name>, <name><surname>Tang</surname><given-names>W</given-names></name>, <name><surname>Xie</surname><given-names>L</given-names></name>, <name><surname>Wang</surname><given-names>J</given-names></name>, <name><surname>Deng</surname><given-names>Y</given-names></name>, <name><surname>Peng</surname><given-names>Q</given-names></name>, <etal>et al</etal><article-title>Prognostic significance of dickkopf-1 overexpression in solid tumors: a meta-analysis</article-title>. <source>Tumour Biol</source>. <year>2014</year>;<volume>35</volume>: <fpage>3145</fpage>–<lpage>3154</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s13277-013-1411-x">10.1007/s13277-013-1411-x</ext-link></comment><pub-id pub-id-type="pmid">24258111</pub-id></mixed-citation></ref><ref id="pone.0171771.ref040"><label>40</label><mixed-citation publication-type="journal"><name><surname>Spillane</surname><given-names>M</given-names></name>, <name><surname>Schwarz</surname><given-names>N</given-names></name>, <name><surname>Willoughby</surname><given-names>DS</given-names></name>. <article-title>Upper-body resistance exercise augments vastus lateralis androgen receptor-DNA binding and canonical Wnt/beta-catenin signaling compared to lower-body resistance exercise in resistance-trained men without an acute increase in serum testosterone</article-title>. <source>Steroids</source>. <year>2015</year>;<volume>98</volume>: <fpage>63</fpage>–<lpage>71</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.steroids.2015.02.019">10.1016/j.steroids.2015.02.019</ext-link></comment><pub-id pub-id-type="pmid">25742735</pub-id></mixed-citation></ref><ref id="pone.0171771.ref041"><label>41</label><mixed-citation publication-type="journal"><name><surname>Xu</surname><given-names>X</given-names></name>, <name><surname>Zhan</surname><given-names>M</given-names></name>, <name><surname>Duan</surname><given-names>W</given-names></name>, <name><surname>Prabhu</surname><given-names>V</given-names></name>, <name><surname>Brenneman</surname><given-names>R</given-names></name>, <name><surname>Wood</surname><given-names>W</given-names></name>, <etal>et al</etal><article-title>Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender</article-title>. <source>Genome Biol</source>. <year>2007</year>;<volume>8</volume>: <fpage>R234</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/gb-2007-8-11-r234">10.1186/gb-2007-8-11-r234</ext-link></comment><pub-id pub-id-type="pmid">17988385</pub-id></mixed-citation></ref><ref id="pone.0171771.ref042"><label>42</label><mixed-citation publication-type="journal"><name><surname>Staal</surname><given-names>FJ</given-names></name>, <name><surname>Luis</surname><given-names>TC</given-names></name>, <name><surname>Tiemessen</surname><given-names>MM</given-names></name>. <article-title>WNT signalling in the immune system: WNT is spreading its wings</article-title>. <source>Nat Rev Immunol</source>. <year>2008</year>;<volume>8</volume>: <fpage>581</fpage>–<lpage>593</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/nri2360">10.1038/nri2360</ext-link></comment><pub-id pub-id-type="pmid">18617885</pub-id></mixed-citation></ref><ref id="pone.0171771.ref043"><label>43</label><mixed-citation publication-type="journal"><name><surname>Gattinoni</surname><given-names>L</given-names></name>, <name><surname>Ji</surname><given-names>Y</given-names></name>, <name><surname>Restifo</surname><given-names>NP</given-names></name>. <article-title>Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy</article-title>. <source>Clin Cancer Res</source>. <year>2010</year>;<volume>16</volume>: <fpage>4695</fpage>–<lpage>4701</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1158/1078-0432.CCR-10-0356">10.1158/1078-0432.CCR-10-0356</ext-link></comment><pub-id pub-id-type="pmid">20688898</pub-id></mixed-citation></ref><ref id="pone.0171771.ref044"><label>44</label><mixed-citation publication-type="journal"><name><surname>Cao Dinh</surname><given-names>H</given-names></name>, <name><surname>Beyer</surname><given-names>I</given-names></name>, <name><surname>Mets</surname><given-names>T</given-names></name>, <name><surname>Onyema</surname><given-names>OO</given-names></name>, <name><surname>Njemini</surname><given-names>R</given-names></name>, <name><surname>Renmans</surname><given-names>W</given-names></name>, <etal>et al</etal><article-title>Effects of physical exercise on markers of cellular immunosenescence: A systematic review</article-title>. <source>Calcif Tissue Int</source>. <year>2016</year></mixed-citation></ref><ref id="pone.0171771.ref045"><label>45</label><mixed-citation publication-type="journal"><name><surname>Veeck</surname><given-names>J</given-names></name>, <name><surname>Niederacher</surname><given-names>D</given-names></name>, <name><surname>An</surname><given-names>H</given-names></name>, <name><surname>Klopocki</surname><given-names>E</given-names></name>, <name><surname>Wiesmann</surname><given-names>F</given-names></name>, <name><surname>Betz</surname><given-names>B</given-names></name>, <etal>et al</etal><article-title>Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis</article-title>. <source>Oncogene</source>. <year>2006</year>;<volume>25</volume>: <fpage>3479</fpage>–<lpage>3488</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.onc.1209386">10.1038/sj.onc.1209386</ext-link></comment><pub-id pub-id-type="pmid">16449975</pub-id></mixed-citation></ref><ref id="pone.0171771.ref046"><label>46</label><mixed-citation publication-type="journal"><name><surname>Suzuki</surname><given-names>H</given-names></name>, <name><surname>Toyota</surname><given-names>M</given-names></name>, <name><surname>Carraway</surname><given-names>H</given-names></name>, <name><surname>Gabrielson</surname><given-names>E</given-names></name>, <name><surname>Ohmura</surname><given-names>T</given-names></name>, <name><surname>Fujikane</surname><given-names>T</given-names></name>, <etal>et al</etal><article-title>Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer</article-title>. <source>Br J Cancer</source>. <year>2008</year>;<volume>98</volume>: <fpage>1147</fpage>–<lpage>1156</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1038/sj.bjc.6604259">10.1038/sj.bjc.6604259</ext-link></comment><pub-id pub-id-type="pmid">18283316</pub-id></mixed-citation></ref><ref id="pone.0171771.ref047"><label>47</label><mixed-citation publication-type="journal"><name><surname>Klopocki</surname><given-names>E</given-names></name>, <name><surname>Kristiansen</surname><given-names>G</given-names></name>, <name><surname>Wild</surname><given-names>PJ</given-names></name>, <name><surname>Klaman</surname><given-names>I</given-names></name>, <name><surname>Castanos-Velez</surname><given-names>E</given-names></name>, <name><surname>Singer</surname><given-names>G</given-names></name>, <etal>et al</etal><article-title>Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors</article-title>. <source>Int J Oncol</source>. <year>2004</year>;<volume>25</volume>: <fpage>641</fpage>–<lpage>649</lpage>. <pub-id pub-id-type="pmid">15289865</pub-id></mixed-citation></ref><ref id="pone.0171771.ref048"><label>48</label><mixed-citation publication-type="journal"><name><surname>Lagathu</surname><given-names>C</given-names></name>, <name><surname>Christodoulides</surname><given-names>C</given-names></name>, <name><surname>Tan</surname><given-names>CY</given-names></name>, <name><surname>Virtue</surname><given-names>S</given-names></name>, <name><surname>Laudes</surname><given-names>M</given-names></name>, <name><surname>Campbell</surname><given-names>M</given-names></name>, <etal>et al</etal><article-title>Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity</article-title>. <source>Int J Obes (Lond)</source>. <year>2010</year>;<volume>34</volume>: <fpage>1695</fpage>–<lpage>1705</lpage>.<pub-id pub-id-type="pmid">20514047</pub-id></mixed-citation></ref><ref id="pone.0171771.ref049"><label>49</label><mixed-citation publication-type="journal"><name><surname>Wang</surname><given-names>M</given-names></name>, <name><surname>Cheng</surname><given-names>N</given-names></name>, <name><surname>Zheng</surname><given-names>S</given-names></name>, <name><surname>Wang</surname><given-names>D</given-names></name>, <name><surname>Hu</surname><given-names>X</given-names></name>, <name><surname>Ren</surname><given-names>X</given-names></name>, <etal>et al</etal><article-title>Metabolic syndrome and the risk of breast cancer among postmenopausal women in north-west China</article-title>. <source>Climacteric</source>. <year>2015</year>;<volume>18</volume>: <fpage>852</fpage>–<lpage>858</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3109/13697137.2015.1071346">10.3109/13697137.2015.1071346</ext-link></comment><pub-id pub-id-type="pmid">26507498</pub-id></mixed-citation></ref><ref id="pone.0171771.ref050"><label>50</label><mixed-citation publication-type="journal"><name><surname>Bhandari</surname><given-names>R</given-names></name>, <name><surname>Kelley</surname><given-names>GA</given-names></name>, <name><surname>Hartley</surname><given-names>TA</given-names></name>, <name><surname>Rockett</surname><given-names>IR</given-names></name>. <article-title>Metabolic syndrome is associated with increased breast cancer risk: a systematic review with meta-analysis</article-title>. <source>Int J Breast Cancer</source>. <year>2014</year>;<volume>2014</volume>: <fpage>189384</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1155/2014/189384">10.1155/2014/189384</ext-link></comment><pub-id pub-id-type="pmid">25653879</pub-id></mixed-citation></ref><ref id="pone.0171771.ref051"><label>51</label><mixed-citation publication-type="journal"><name><surname>Mauro</surname><given-names>L</given-names></name>, <name><surname>Naimo</surname><given-names>GD</given-names></name>, <name><surname>Ricchio</surname><given-names>E</given-names></name>, <name><surname>Panno</surname><given-names>ML</given-names></name>, <name><surname>Ando</surname><given-names>S</given-names></name>. <article-title>Cross-Talk between Adiponectin and IGF-IR in Breast Cancer</article-title>. <source>Front Oncol</source>. <year>2015</year>;<volume>5</volume>: <fpage>157</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3389/fonc.2015.00157">10.3389/fonc.2015.00157</ext-link></comment><pub-id pub-id-type="pmid">26236690</pub-id></mixed-citation></ref><ref id="pone.0171771.ref052"><label>52</label><mixed-citation publication-type="journal"><name><surname>Giannopoulou</surname><given-names>I</given-names></name>, <name><surname>Fernhall</surname><given-names>B</given-names></name>, <name><surname>Carhart</surname><given-names>R</given-names></name>, <name><surname>Weinstock</surname><given-names>RS</given-names></name>, <name><surname>Baynard</surname><given-names>T</given-names></name>, <name><surname>Figueroa</surname><given-names>A</given-names></name>, <etal>et al</etal><article-title>Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes</article-title>. <source>Metabolism</source>. <year>2005</year>;<volume>54</volume>: <fpage>866</fpage>–<lpage>875</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.metabol.2005.01.033">10.1016/j.metabol.2005.01.033</ext-link></comment><pub-id pub-id-type="pmid">15988694</pub-id></mixed-citation></ref><ref id="pone.0171771.ref053"><label>53</label><mixed-citation publication-type="journal"><name><surname>Befort</surname><given-names>CA</given-names></name>, <name><surname>Klemp</surname><given-names>JR</given-names></name>, <name><surname>Austin</surname><given-names>HL</given-names></name>, <name><surname>Perri</surname><given-names>MG</given-names></name>, <name><surname>Schmitz</surname><given-names>KH</given-names></name>, <name><surname>Sullivan</surname><given-names>DK</given-names></name>, <etal>et al</etal><article-title>Outcomes of a weight loss intervention among rural breast cancer survivors</article-title>. <source>Breast Cancer Res Treat</source>. <year>2012</year>;<volume>132</volume>: <fpage>631</fpage>–<lpage>639</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1007/s10549-011-1922-3">10.1007/s10549-011-1922-3</ext-link></comment><pub-id pub-id-type="pmid">22198470</pub-id></mixed-citation></ref><ref id="pone.0171771.ref054"><label>54</label><mixed-citation publication-type="journal"><name><surname>DeCensi</surname><given-names>A</given-names></name>, <name><surname>Gennari</surname><given-names>A</given-names></name>. <article-title>Insulin breast cancer connection: confirmatory data set the stage for better care</article-title>. <source>J Clin Oncol</source>. <year>2011</year>;<volume>29</volume>: <fpage>7</fpage>–<lpage>10</lpage>.</mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 004416 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 004416 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= LymphedemaV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:5298304
|texte= Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:28178355" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a LymphedemaV1
| This area was generated with Dilib version V0.6.31. |  |