Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer
Identifieur interne : 001383 ( Main/Exploration ); précédent : 001382; suivant : 001384Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer
Auteurs : Johanna Tuomela [États-Unis] ; Jouko Sandholm [États-Unis] ; Peeter Karihtala [Finlande] ; Joanna Ilvesaro [États-Unis] ; Katri S. Vuopala [Finlande] ; Joonas H. Kauppila [Finlande] ; Saila Kauppila [Finlande] ; Dongquan Chen [États-Unis] ; Christine Pressey [États-Unis] ; Pirkko H Rkönen [Finlande] ; Kevin W. Harris [États-Unis] ; David Graves [États-Unis] ; P Ivi K. Auvinen [Finlande] ; Ylermi Soini [Finlande] ; Arja Jukkola-Vuorinen [Finlande] ; Katri S. Selander [États-Unis]Source :
- Breast Cancer Research and Treatment [ 0167-6806 ] ; 2012-09-01.
English descriptors
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Abstract
Abstract: Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.
Url:
DOI: 10.1007/s10549-012-2181-7
Affiliations:
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Vuopala</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology, Lapland Central Hospital, Rovaniemi</wicri:regionArea><wicri:noRegion>Rovaniemi</wicri:noRegion></affiliation></author><author><name sortKey="Kauppila, Joonas H" sort="Kauppila, Joonas H" uniqKey="Kauppila J" first="Joonas H." last="Kauppila">Joonas H. Kauppila</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology, Oulu University Hospital, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Surgery, Oulu University Hospital, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Anatomy & Cell Biology, University of Oulu, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Kauppila, Saila" sort="Kauppila, Saila" uniqKey="Kauppila S" first="Saila" last="Kauppila">Saila Kauppila</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology, Oulu University Hospital, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Dongquan" sort="Chen, Dongquan" uniqKey="Chen D" first="Dongquan" last="Chen">Dongquan Chen</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, 35294-3300, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Pressey, Christine" sort="Pressey, Christine" uniqKey="Pressey C" first="Christine" last="Pressey">Christine Pressey</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, 35294-3300, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="H Rkonen, Pirkko" sort="H Rkonen, Pirkko" uniqKey="H Rkonen P" first="Pirkko" last="H Rkönen">Pirkko H Rkönen</name><affiliation wicri:level="4"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Cell Biology and Anatomy, University of Turku, Turku</wicri:regionArea><placeName><settlement type="city">Turku</settlement><region type="région" nuts="2">Finlande occidentale</region></placeName><orgName type="university">Université de Turku</orgName></affiliation></author><author><name sortKey="Harris, Kevin W" sort="Harris, Kevin W" uniqKey="Harris K" first="Kevin W." last="Harris">Kevin W. Harris</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, 35294-3300, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Birmingham Veterans Affairs Medical Center, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Graves, David" sort="Graves, David" uniqKey="Graves D" first="David" last="Graves">David Graves</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Auvinen, P Ivi K" sort="Auvinen, P Ivi K" uniqKey="Auvinen P" first="P Ivi K." last="Auvinen">P Ivi K. Auvinen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Oncology, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Soini, Ylermi" sort="Soini, Ylermi" uniqKey="Soini Y" first="Ylermi" last="Soini">Ylermi Soini</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Jukkola Vuorinen, Arja" sort="Jukkola Vuorinen, Arja" uniqKey="Jukkola Vuorinen A" first="Arja" last="Jukkola-Vuorinen">Arja Jukkola-Vuorinen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Selander, Katri S" sort="Selander, Katri S" uniqKey="Selander K" first="Katri S." last="Selander">Katri S. Selander</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, 35294-3300, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Breast Cancer Research and Treatment</title><title level="j" type="abbrev">Breast Cancer Res Treat</title><idno type="ISSN">0167-6806</idno><idno type="eISSN">1573-7217</idno><imprint><publisher>Springer US; http://www.springer-ny.com</publisher><pubPlace>Boston</pubPlace><date type="published" when="2012-09-01">2012-09-01</date><biblScope unit="volume">135</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="481">481</biblScope><biblScope unit="page" to="493">493</biblScope></imprint><idno type="ISSN">0167-6806</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0167-6806</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Breast cancer</term><term>Hypoxia</term><term>Invasion</term><term>Toll-like receptor-9</term><term>Triple negative</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.</div></front></TEI><affiliations><list><country><li>Finlande</li><li>États-Unis</li></country><region><li>Alabama</li><li>Finlande occidentale</li></region><settlement><li>Turku</li></settlement><orgName><li>Université de Turku</li></orgName></list><tree><country name="États-Unis"><region name="Alabama"><name sortKey="Tuomela, Johanna" sort="Tuomela, Johanna" uniqKey="Tuomela J" first="Johanna" last="Tuomela">Johanna Tuomela</name></region><name sortKey="Chen, Dongquan" sort="Chen, Dongquan" uniqKey="Chen D" first="Dongquan" last="Chen">Dongquan Chen</name><name sortKey="Chen, Dongquan" sort="Chen, Dongquan" uniqKey="Chen D" first="Dongquan" last="Chen">Dongquan Chen</name><name sortKey="Graves, David" sort="Graves, David" uniqKey="Graves D" first="David" last="Graves">David Graves</name><name sortKey="Graves, David" sort="Graves, David" uniqKey="Graves D" first="David" last="Graves">David Graves</name><name sortKey="Harris, Kevin W" sort="Harris, Kevin W" uniqKey="Harris K" first="Kevin W." last="Harris">Kevin W. Harris</name><name sortKey="Harris, Kevin W" sort="Harris, Kevin W" uniqKey="Harris K" first="Kevin W." last="Harris">Kevin W. Harris</name><name sortKey="Harris, Kevin W" sort="Harris, Kevin W" uniqKey="Harris K" first="Kevin W." last="Harris">Kevin W. Harris</name><name sortKey="Ilvesaro, Joanna" sort="Ilvesaro, Joanna" uniqKey="Ilvesaro J" first="Joanna" last="Ilvesaro">Joanna Ilvesaro</name><name sortKey="Ilvesaro, Joanna" sort="Ilvesaro, Joanna" uniqKey="Ilvesaro J" first="Joanna" last="Ilvesaro">Joanna Ilvesaro</name><name sortKey="Pressey, Christine" sort="Pressey, Christine" uniqKey="Pressey C" first="Christine" last="Pressey">Christine Pressey</name><name sortKey="Pressey, Christine" sort="Pressey, Christine" uniqKey="Pressey C" first="Christine" last="Pressey">Christine Pressey</name><name sortKey="Sandholm, Jouko" sort="Sandholm, Jouko" uniqKey="Sandholm J" first="Jouko" last="Sandholm">Jouko Sandholm</name><name sortKey="Sandholm, Jouko" sort="Sandholm, Jouko" uniqKey="Sandholm J" first="Jouko" last="Sandholm">Jouko Sandholm</name><name sortKey="Selander, Katri S" sort="Selander, Katri S" uniqKey="Selander K" first="Katri S." last="Selander">Katri S. Selander</name><name sortKey="Selander, Katri S" sort="Selander, Katri S" uniqKey="Selander K" first="Katri S." last="Selander">Katri S. Selander</name><name sortKey="Selander, Katri S" sort="Selander, Katri S" uniqKey="Selander K" first="Katri S." last="Selander">Katri S. Selander</name><name sortKey="Tuomela, Johanna" sort="Tuomela, Johanna" uniqKey="Tuomela J" first="Johanna" last="Tuomela">Johanna Tuomela</name></country><country name="Finlande"><noRegion><name sortKey="Karihtala, Peeter" sort="Karihtala, Peeter" uniqKey="Karihtala P" first="Peeter" last="Karihtala">Peeter Karihtala</name></noRegion><name sortKey="Auvinen, P Ivi K" sort="Auvinen, P Ivi K" uniqKey="Auvinen P" first="P Ivi K." last="Auvinen">P Ivi K. Auvinen</name><name sortKey="H Rkonen, Pirkko" sort="H Rkonen, Pirkko" uniqKey="H Rkonen P" first="Pirkko" last="H Rkönen">Pirkko H Rkönen</name><name sortKey="Jukkola Vuorinen, Arja" sort="Jukkola Vuorinen, Arja" uniqKey="Jukkola Vuorinen A" first="Arja" last="Jukkola-Vuorinen">Arja Jukkola-Vuorinen</name><name sortKey="Kauppila, Joonas H" sort="Kauppila, Joonas H" uniqKey="Kauppila J" first="Joonas H." last="Kauppila">Joonas H. Kauppila</name><name sortKey="Kauppila, Joonas H" sort="Kauppila, Joonas H" uniqKey="Kauppila J" first="Joonas H." last="Kauppila">Joonas H. Kauppila</name><name sortKey="Kauppila, Joonas H" sort="Kauppila, Joonas H" uniqKey="Kauppila J" first="Joonas H." last="Kauppila">Joonas H. Kauppila</name><name sortKey="Kauppila, Saila" sort="Kauppila, Saila" uniqKey="Kauppila S" first="Saila" last="Kauppila">Saila Kauppila</name><name sortKey="Soini, Ylermi" sort="Soini, Ylermi" uniqKey="Soini Y" first="Ylermi" last="Soini">Ylermi Soini</name><name sortKey="Vuopala, Katri S" sort="Vuopala, Katri S" uniqKey="Vuopala K" first="Katri S." last="Vuopala">Katri S. Vuopala</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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