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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</title><author><name sortKey="Czogalla, Bastian" sort="Czogalla, Bastian" uniqKey="Czogalla B" first="Bastian" last="Czogalla">Bastian Czogalla</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kahaly, Maja" sort="Kahaly, Maja" uniqKey="Kahaly M" first="Maja" last="Kahaly">Maja Kahaly</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Mayr, Doris" sort="Mayr, Doris" uniqKey="Mayr D" first="Doris" last="Mayr">Doris Mayr</name><affiliation><nlm:aff id="AFF0002"><institution>Faculty of Medicine, Institute of Pathology, Lmu Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Schmoeckel, Elisa" sort="Schmoeckel, Elisa" uniqKey="Schmoeckel E" first="Elisa" last="Schmoeckel">Elisa Schmoeckel</name><affiliation><nlm:aff id="AFF0002"><institution>Faculty of Medicine, Institute of Pathology, Lmu Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Niesler, Beate" sort="Niesler, Beate" uniqKey="Niesler B" first="Beate" last="Niesler">Beate Niesler</name><affiliation><nlm:aff id="AFF0003"><institution>Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg</institution>,<addr-line>Heidelberg</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hester, Anna" sort="Hester, Anna" uniqKey="Hester A" first="Anna" last="Hester">Anna Hester</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Zeder Go, Christine" sort="Zeder Go, Christine" uniqKey="Zeder Go C" first="Christine" last="Zeder-Gö">Christine Zeder-Gö</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kolben, Thomas" sort="Kolben, Thomas" uniqKey="Kolben T" first="Thomas" last="Kolben">Thomas Kolben</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Burges, Alexander" sort="Burges, Alexander" uniqKey="Burges A" first="Alexander" last="Burges">Alexander Burges</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Mahner, Sven" sort="Mahner, Sven" uniqKey="Mahner S" first="Sven" last="Mahner">Sven Mahner</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jeschke, Udo" sort="Jeschke, Udo" uniqKey="Jeschke U" first="Udo" last="Jeschke">Udo Jeschke</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Trillsch, Fabian" sort="Trillsch, Fabian" uniqKey="Trillsch F" first="Fabian" last="Trillsch">Fabian Trillsch</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31616183</idno><idno type="pmc">6699153</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699153</idno><idno type="RBID">PMC:6699153</idno><idno type="doi">10.2147/CMAR.S210004</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000443</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000443</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</title><author><name sortKey="Czogalla, Bastian" sort="Czogalla, Bastian" uniqKey="Czogalla B" first="Bastian" last="Czogalla">Bastian Czogalla</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kahaly, Maja" sort="Kahaly, Maja" uniqKey="Kahaly M" first="Maja" last="Kahaly">Maja Kahaly</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Mayr, Doris" sort="Mayr, Doris" uniqKey="Mayr D" first="Doris" last="Mayr">Doris Mayr</name><affiliation><nlm:aff id="AFF0002"><institution>Faculty of Medicine, Institute of Pathology, Lmu Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Schmoeckel, Elisa" sort="Schmoeckel, Elisa" uniqKey="Schmoeckel E" first="Elisa" last="Schmoeckel">Elisa Schmoeckel</name><affiliation><nlm:aff id="AFF0002"><institution>Faculty of Medicine, Institute of Pathology, Lmu Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Niesler, Beate" sort="Niesler, Beate" uniqKey="Niesler B" first="Beate" last="Niesler">Beate Niesler</name><affiliation><nlm:aff id="AFF0003"><institution>Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg</institution>,<addr-line>Heidelberg</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hester, Anna" sort="Hester, Anna" uniqKey="Hester A" first="Anna" last="Hester">Anna Hester</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Zeder Go, Christine" sort="Zeder Go, Christine" uniqKey="Zeder Go C" first="Christine" last="Zeder-Gö">Christine Zeder-Gö</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kolben, Thomas" sort="Kolben, Thomas" uniqKey="Kolben T" first="Thomas" last="Kolben">Thomas Kolben</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Burges, Alexander" sort="Burges, Alexander" uniqKey="Burges A" first="Alexander" last="Burges">Alexander Burges</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Mahner, Sven" sort="Mahner, Sven" uniqKey="Mahner S" first="Sven" last="Mahner">Sven Mahner</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jeschke, Udo" sort="Jeschke, Udo" uniqKey="Jeschke U" first="Udo" last="Jeschke">Udo Jeschke</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Trillsch, Fabian" sort="Trillsch, Fabian" uniqKey="Trillsch F" first="Fabian" last="Trillsch">Fabian Trillsch</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author></analytic><series><title level="j">Cancer Management and Research</title><idno type="eISSN">1179-1322</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S2001"><title>Purpose</title><p>This study aimed to investigate the potential prognostic impact of nuclear factor erythroid 2-related factor 2 (NRF2) and progesterone receptor A (PRA)/progesterone receptor B (PRB) in ovarian cancer patients which might be the rationale for putative new treatment strategies.</p></sec><sec id="S2002"><title>Patients and methods</title><p>The presence of NRF2 and PRA/PRB was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining of NRF2 and PRA/PRB was rated using the semi-quantitative immunoreactive score (IR score, Remmele’s score) and correlated to clinical and pathological data. NRF2 and PRA/PRB expression were compared with respect to the overall survival (OS).</p></sec><sec id="S2003"><title>Results</title><p>NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes (<italic>p</italic>=0.001 and <italic>p</italic>=0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes (<italic>p</italic>=0.02). Histological subtypes showed no significant differences in the PRB expression. A strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, <italic>p</italic>=0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, <italic>p</italic>=0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; <italic>p</italic>=0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; <italic>p</italic>=0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; <italic>p</italic>=0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; <italic>p</italic>=0.02). The same relationship was also noted for NRF2 and PRB with improved OS for patients expressing both cytoplasmic NRF2 and PRB (median 153.5 vs 30.6 months; <italic>p</italic>=0.009). Silencing of <italic>NFE2L2</italic> induced higher mRNA expression of <italic>PGR</italic> in the cancer cell line OVCAR3 (<italic>p</italic>>0.05) confirming genetic interactions of NRF2 and PR.</p></sec><sec id="S2004"><title>Conclusion</title><p>In this study, the combination of cytoplasmic NRF2 and high PRA/PRB expression was demonstrated to be associated with improved overall survival in ovarian cancer patients. Further understanding of interactions within the NRF2/AKR1C1/PR pathway could open new additional therapeutic approaches.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></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">Cancer Manag Res</journal-id><journal-id journal-id-type="iso-abbrev">Cancer Manag Res</journal-id><journal-id journal-id-type="publisher-id">CMAR</journal-id><journal-id journal-id-type="pmc">cancmanres</journal-id><journal-title-group><journal-title>Cancer Management and Research</journal-title></journal-title-group><issn pub-type="epub">1179-1322</issn><publisher><publisher-name>Dove</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31616183</article-id><article-id pub-id-type="pmc">6699153</article-id><article-id pub-id-type="publisher-id">210004</article-id><article-id pub-id-type="doi">10.2147/CMAR.S210004</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject></subj-group></article-categories><title-group><article-title>Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</article-title><alt-title alt-title-type="running-authors">Czogalla et al</alt-title><alt-title alt-title-type="running-title">Czogalla et al</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Czogalla</surname><given-names>Bastian</given-names></name><xref ref-type="corresp" rid="AN0001"></xref><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Kahaly</surname><given-names>Maja</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Mayr</surname><given-names>Doris</given-names></name><xref ref-type="aff" rid="AFF0002">2</xref></contrib><contrib contrib-type="author"><name><surname>Schmoeckel</surname><given-names>Elisa</given-names></name><xref ref-type="aff" rid="AFF0002">2</xref></contrib><contrib contrib-type="author"><name><surname>Niesler</surname><given-names>Beate</given-names></name><xref ref-type="aff" rid="AFF0003">3</xref></contrib><contrib contrib-type="author"><name><surname>Hester</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Zeder-Göß</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Kolben</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Burges</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Mahner</surname><given-names>Sven</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Jeschke</surname><given-names>Udo</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Trillsch</surname><given-names>Fabian</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><aff id="AFF0001"><label>1</label><institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></aff><aff id="AFF0002"><label>2</label><institution>Faculty of Medicine, Institute of Pathology, Lmu Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></aff><aff id="AFF0003"><label>3</label><institution>Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg</institution>,<addr-line>Heidelberg</addr-line>,<country>Germany</country></aff></contrib-group><author-notes><corresp id="AN0001">Correspondence: Bastian Czogalla<institution>Department of Obstetrics and Gynecology, University Hospital, LMU Munich</institution>, <addr-line>Marchioninistr 15</addr-line>, <addr-line>Munich</addr-line><addr-line>81377</addr-line>, <country>Germany</country><phone>Tel +49 8 944 007 4775</phone><fax>Fax +49 8 944 007 2051</fax>Email Bastian.Czogalla@med.uni-muenchen.de</corresp></author-notes><pub-date pub-type="epub"><day>14</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>11</volume><fpage>7673</fpage><lpage>7684</lpage><history><date date-type="received"><day>26</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>27</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Czogalla et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Czogalla et al.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at <ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link> and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (<ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>).</license-p></license></permissions><abstract><sec id="S2001"><title>Purpose</title><p>This study aimed to investigate the potential prognostic impact of nuclear factor erythroid 2-related factor 2 (NRF2) and progesterone receptor A (PRA)/progesterone receptor B (PRB) in ovarian cancer patients which might be the rationale for putative new treatment strategies.</p></sec><sec id="S2002"><title>Patients and methods</title><p>The presence of NRF2 and PRA/PRB was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining of NRF2 and PRA/PRB was rated using the semi-quantitative immunoreactive score (IR score, Remmele’s score) and correlated to clinical and pathological data. NRF2 and PRA/PRB expression were compared with respect to the overall survival (OS).</p></sec><sec id="S2003"><title>Results</title><p>NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes (<italic>p</italic>=0.001 and <italic>p</italic>=0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes (<italic>p</italic>=0.02). Histological subtypes showed no significant differences in the PRB expression. A strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, <italic>p</italic>=0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, <italic>p</italic>=0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; <italic>p</italic>=0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; <italic>p</italic>=0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; <italic>p</italic>=0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; <italic>p</italic>=0.02). The same relationship was also noted for NRF2 and PRB with improved OS for patients expressing both cytoplasmic NRF2 and PRB (median 153.5 vs 30.6 months; <italic>p</italic>=0.009). Silencing of <italic>NFE2L2</italic> induced higher mRNA expression of <italic>PGR</italic> in the cancer cell line OVCAR3 (<italic>p</italic>>0.05) confirming genetic interactions of NRF2 and PR.</p></sec><sec id="S2004"><title>Conclusion</title><p>In this study, the combination of cytoplasmic NRF2 and high PRA/PRB expression was demonstrated to be associated with improved overall survival in ovarian cancer patients. Further understanding of interactions within the NRF2/AKR1C1/PR pathway could open new additional therapeutic approaches.</p></sec></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>nuclear factor erythroid 2-related factor 2</kwd><kwd>progesterone receptor</kwd><kwd>ovarian cancer</kwd><kwd>immunohistochemistry</kwd></kwd-group><counts><fig-count count="6"></fig-count><table-count count="3"></table-count><ref-count count="65"></ref-count><page-count count="12"></page-count></counts></article-meta></front><body><sec sec-type="intro" id="S0001"><title>Introduction</title><p>Ovarian cancer is one of the five most frequent cancer deaths among women with a five-year survival rate of less than 45%.<xref rid="CIT0001" ref-type="bibr">1</xref>,<xref rid="CIT0002" ref-type="bibr">2</xref> The non-specific symptoms combined with an insufficient screening method often lead to a diagnosis in advanced tumor stage with a consecutively impaired prognosis. Recommended therapeutic approaches include primary cytoreductive surgery and platinum-based chemotherapy with anti-angiogenic agents or PARP inhibitors. Most reliable prognostic markers include volume of residual disease after initial debulking surgery, the International Federation of Gynecology and Obstetrics (FIGO) stage, ascites volume, patient age, and histological subtype.<xref rid="CIT0003" ref-type="bibr">3</xref>–<xref rid="CIT0006" ref-type="bibr">6</xref> Epithelial ovarian carcinomas (EOC) are classified as serous, mucinous, endometrioid, and clear-cell histology, being distinguished in terms of phenotype, molecular background, and etiology.<xref rid="CIT0007" ref-type="bibr">7</xref> Research to identify new molecular prognostic markers needs to take this heterogeneity of ovarian cancer into account. A better understanding of the differences between ovarian cancer subtypes appears crucial to enable new diagnostic and therapeutic approaches.<fig id="F0002" fig-type="figure" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Double immunofluorescence of NRF2 and PRB.</p><p><bold>Notes:</bold> Red stained cytoplasmic NRF2 expression, green stained PRB expression in ovarian cancer tissue. Co-expression of NRF2 and PRB + DAPI (triple filter excitation)</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0001"></graphic></fig></p><p>Current investigations attribute an important impact for the development of ovarian cancer to oxidative stress.<xref rid="CIT0008" ref-type="bibr">8</xref> The nuclear factor erythroid-2-related factor 2 (NRF2) is a well-known regulator of antioxidant and cytoprotective genes mediating cellular coping of oxidative stress. Whereas NRF2 is ubiquitously expressed at low levels in all human organs, tight regulation of this major cellular defense mechanism is crucial to maintain cellular homeostasis. Different cancer entities and cell lines exhibit high constitutive levels of NRF2.<xref rid="CIT0009" ref-type="bibr">9</xref>–<xref rid="CIT0013" ref-type="bibr">13</xref> Our research group recently demonstrated that cytoplasmic NRF2 expression in its inactive cytoplasmic form is associated with improved survival in ovarian cancer patients.<xref rid="CIT0014" ref-type="bibr">14</xref> Overexpression of NRF2 might protect cancer cells from the cytotoxic effects of anticancer therapies, resulting in resistance to chemo- and radiotherapy.<xref rid="CIT0015" ref-type="bibr">15</xref>,<xref rid="CIT0016" ref-type="bibr">16</xref></p><p>Progesterone inhibits cell growth and metastasis in ovarian cancer cells and is considered as an established protective factor for the development of ovarian cancer as part of combined oral contraceptives.<xref rid="CIT0017" ref-type="bibr">17</xref>–<xref rid="CIT0020" ref-type="bibr">20</xref> The detailed molecular background of this mechanism has not yet been fully understood. The progesterone receptor (PR), a member of the steroid hormone receptor superfamily, is expressed in two isoforms, the PRA and PRB differing in their molecular weight. Studies show an up to date functional unknown dominant expression of PRB in ovarian carcinomas.<xref rid="CIT0021" ref-type="bibr">21</xref>–<xref rid="CIT0023" ref-type="bibr">23</xref> Progesterone receptor expression has been described to be associated with improved overall (OS) and progression-free survival (PFS) due to its putative anti-proliferative effect.<xref rid="CIT0024" ref-type="bibr">24</xref>–<xref rid="CIT0027" ref-type="bibr">27</xref> To our knowledge, interactions between NRF2 and PR are not well understood so far, but warrant further investigation based on the results of our present data.</p><p>This study aimed to investigate the potential prognostic impact of NRF2 and PR in ovarian cancer patients which might be the rationale for putative new treatment strategies.</p></sec><sec id="S0002"><title>Materials and methods</title><sec id="S0002-S2001"><title>Patients and specimens</title><p>Tissue samples of 156 patients who underwent surgery for EOC at the Department of Obstetrics and Gynecology, Ludwig-Maximillian’s-University Munich from 1990 to 2002, were analyzed in this study. Clinical data were obtained from the patient’s charts and follow-up data from the Munich Cancer Registry. All samples had been formalin-fixated and paraffin-embedded (FFPE). Patients with benign or borderline tumors were excluded and no patients had neoadjuvant chemotherapy. Specialized pathologists for EOC examined and classified the samples for tumor grading: low (n=38), high (n=117), and histological subtypes: serous (n=110), endometrioid (n=21), clear cell (n=12), mucinous (n=13). Staging was performed using TNM and FIGO (WHO) classification: I (n=35), II (n=10,) III (n=103), IV (n=3). Data on primary tumor extension were available in 155 cases: T1 (n=40), T2 (n=18), T3 (n=93), T4 (n=4) as well as data on lymph node involvement in 95 cases N0 (n=43), N1 (n=52). Data on distant metastasis were available in nine cases M0 (n=3), M1 (n=6).</p></sec><sec id="S0002-S2002"><title>Ethical approval</title><p>This study was approved by the Ethics Committee of the Ludwig-Maximilians-University, Munich, Germany (approval number 227-09). All tissue samples used for this study were obtained from material from the archives of the Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany, initially used for pathological diagnostics. The diagnostic procedures were completed before the current study was performed. All patients´ data were fully anonymized, and the study was performed according to the standards set in the Declaration of Helsinki 1975. The ethics committee approved this consent process. During the analysis, the observers were fully blinded for patients’ data.</p></sec><sec id="S0002-S2003"><title>Immunohistochemistry</title><p>Immunohistochemistry was performed as previously described by our lab.<xref rid="CIT0028" ref-type="bibr">28</xref> For NRF2 staining, paraffin-embedded and formalin-fixed EOC samples were incubated with Anti-NRF2 (Abcam, Cambridge, UK, rabbit, monoclonal, clone EP1808) at a final concentration of 5.93 µg/mL (1:100 dilution) for 1 hr at room temperature. Afterward, slides were incubated with isotype-matching MACH 3 Rabbit AP Polymer Detection (Biocare Medical, Pacheco, CA, USA, catalog-number M3R533). The Permanent AP Red Kit (Zytomed Systems GmbH, Berlin, Germany, catalog-number ZUC-001) was used as chromogen. Slides were then counterstained with Gill´s hematoxylin (Vector Laboratories, Burlingame, CA, USA). System controls were included.</p><p>For the detection of PR, paraffin-fixed tissue sections were dewaxed with xylol for 15 mins, then dehydrated in ascending concentrations of alcohol (70–100%). Afterward, they were exposed for epitope retrieval for 10 mins in a pressure cooker using sodium citrate buffer (pH 6.0) containing 0.1 M citric acid and 0.1 M sodium citrate in distilled water. After cooling, slides were washed in PBS twice. Endogenous peroxidase activity was quenched by dipping in 3% hydrogen peroxide (Merck, Darmstadt, Germany) in methanol for 20 mins. Non-specific binding of the primary antibodies was blocked by incubating the sections with “diluted normal serum” (10 mL PBS containing 150 μL horse serum; Vector Laboratories, CA) for 20 mins at room temperature. Then, slides were incubated with the primary antibodies (PRA: 1:250 dilutions, Sigma-Aldrich, St. Louis, MO, USA, rabbit, polyclonal, clone R04125; PRB: 1:50 dilutions, Novocastra Reagents, Wetzlar, Germany, mouse, monoclonal, clone SAN27) at room temperature for 60 mins. After washing with PBS, slides were incubated in diluted biotinylated anti-serum secondary antibody (10 mL PBS containing 50 μl horse serum, Vector Laboratories, CA) for 30 mins at room temperature. After incubation with the avidin-biotin-peroxidase complex (diluted in 10 mL PBS, Vector Laboratories, CA) for 30 mins and repeated PBS washing, visualization was conducted using substrate and chromagen 3,3ʹ-diaminobenzidine (DAB; Dako, Glostrup, Denmark, catalog-number K3468) for 8–10 mins. Slides were then counterstained with Mayer’s acidic hematoxylin (Waldeck-Chroma, Münster, Germany, catalog-number 2E-038) and dehydrated in an ascending series of alcohol followed by xylol. System controls were included.</p></sec><sec id="S0002-S2004"><title>Staining evaluation</title><p>All EOC specimens were examined with a Leitz (Wetzlar, Germany) photomicroscope and specific NRF2 and PR immunohistochemically staining reaction was observed in the nuclei and cytoplasm of the cells. The intensity and distribution pattern of NRF2 and PR staining were rated using the semi-quantitative immunoreactive score (IR score, Remmele’s score). To obtain the IR score result, the optional staining intensity (0=no, 1=weak, 2=moderate, and 3=strong staining) and the percentage of positive-stained cells (0=no staining, 1=<10% of the cells, 2=11–50% of the cells, 3=51–80% of the cells, and 4≤81%) were multiplied. NRF2 staining was successfully performed in 145 (93%) of 156 EOC tissue specimens. Cut-off points for the IR scores were selected for the cytoplasmic and nuclear NRF2 staining considering the distribution pattern of IR scores in the collective. Nuclear and cytoplasmic NRF2 staining were regarded as negative with an IR score 0–2, as low with IRS 4–8, and as high with IRS >8. PRA and PRB stainings were successfully performed in all 156 (100%) EOC specimens. Cellular PRA and PRB stainings were considered as negative with an IR score 0 and as positive with IRS >0.</p></sec><sec id="S0002-S2005"><title>Immunofluorescence staining</title><p>Mouse anti-NRF2 IgGs were diluted at 1:200 with a diluting medium (Dako, Hamburg, Germany), while rabbit anti-PRB polyclonal IgGs were diluted at 1:200. After washing, slides were incubated with Cy2-/Cy3-labeled antibodies (Dianova, Hamburg, Germany) as fluorescent secondary antibodies for 30 mins at room temperature in darkness to avoid fluorescence quenching. Cy2-labeled secondary antibodies were used at a dilution of 1:100 and Cy3-labeled antibodies at a dilution of 1:500. Finally, the slides were embedded in mounting buffer containing 4′,6-diamino-2-phenylindole (DAPI, Vectastain, Vector Laboratories) for blue staining of the nucleus after washing and drying. Confocal laser scanning microscope images were acquired with Zeiss LSM 880 with Airyscan model for high-resolution visualization and analyzed with ZEN blue software.</p></sec><sec id="S0002-S2006"><title>Cell line</title><p>The human serous ovarian cancer cell line OVCAR3 was purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA). Cells were maintained in culture in RPMI 1640 medium (ThermoFisher Scientific, Waltham, MA, USA) supplemented with 10% FBS in a humified incubator at 37°C under 5% CO<sub>2</sub>.</p></sec><sec id="S0002-S2007"><title>PCR</title><p>RNA isolation was performed using the RNeasy Mini Kit (Qiagen, Venlo, Netherlands) and 1 µg RNA was converted into first-strand cDNA using the MMLV Reverse Transcriptase 1st-Strand cDNA Synthesis Kit (Epicentre, Madison, WI, USA) according to the instructions of the manufacturer. The basal mRNA expressions of NFE2L2 and PGR were quantified by qPCR applying FastStart Essential DNA Probes Master and gene-specific primers (Roche, Basel, Switzerland). For normalization of expressions the housekeeping genes <italic>β-Actin</italic> and <italic>GAPDH</italic> were used as reference controls.</p></sec><sec id="S0002-S2008"><title>si-RNA</title><p>The specific siRNA for <italic>NFE2L2</italic> (Silencer Select Pre-designed and Custom Designed siRNA, Ambion, Carlsbad, CA, USA) was kindly provided by Beate Niesler (Department of Human Molecular Genetics, University of Heidelberg). Cells were transfected with siRNA using Lipofectamine RNAiMAX reagent (Invitrogen, Carlsbad, CA, USA) to silence the expression of <italic>NFE2L2</italic> in the cell line. RNA Isolation and mRNA quantification by qPCR was repeated as outlined earlier. mRNA expression levels of <italic>NFE2L2</italic> and <italic>PGR</italic> in <italic>NFE2L2</italic> downregulated cells were compared with NFE2L2 containing cells.</p></sec><sec id="S0002-S2009"><title>Statistical analysis</title><p>Statistical analysis was performed using SPSS 25.0 (v25, IBM, Armonk, New York). Distribution of clinical pathological variables was evaluated with the Chi-Square test. Mann–Whitney U test was used to compare IR scores of NRF2/PR between different clinical and pathological subgroups. Correlations between findings of immunohistochemically staining were calculated using Spearman’s analysis. Survival times were analyzed by Kaplan–Meier (log-rank) estimates. To identify an appropriate cut-off, the ROC curve was drawn which is considered as one of the most reliable methods for cut-off point selection. In this context, the ROC curve is a plot representing sensitivity on the <italic>y</italic>-axis and (1-specificity) on the <italic>x</italic>-axis.<xref rid="CIT0029" ref-type="bibr">29</xref> Consecutively, Youden index, defined as the maximum (sensitivity+specificity-1),<xref rid="CIT0030" ref-type="bibr">30</xref> was used to find the optimal cut-off maximizing the sum of sensitivity and specificity.<xref rid="CIT0031" ref-type="bibr">31</xref>,<xref rid="CIT0032" ref-type="bibr">32</xref> For multivariate analyses, a Cox-regression model was applied, with <italic>P</italic>-values less than 0.05 considered to be significant. Ct values of each gene were obtained with qPCR and the relative expressions were calculated using the 2<sup>−ΔΔCt</sup> formula. Statistical data were acquired using Graph Pad Prism 7.03 (v7, La Jolla, California).</p></sec></sec><sec id="S0003"><title>Results</title><sec id="S0003-S2001"><title>NRF2/PR expression correlates with clinical and pathological data</title><p>Clinicopathologic characteristics of the analyzed ovarian cancer patients are listed in <xref rid="T0001" ref-type="table">Table 1</xref>. Nuclear staining of NRF2 was observed in 144 of 145 evaluable cases (99%), and cytoplasmic staining of NRF2 was observed in 139 (96%) of these 145 cases. Median (range) immunoreactivity scores (IRS) for NRF2 in nuclei and cytoplasm were 8 (2,12) and 8 (4,12), respectively.<table-wrap id="T0001" orientation="portrait" position="float"><label>Table 1</label><caption><p>Clinicopathologic characteristics of the ovarian cancer patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Clinicopathologic parameters</th><th rowspan="1" colspan="1">N</th><th rowspan="1" colspan="1">Percentage</th></tr></thead><tbody><tr><td rowspan="1" colspan="1"><bold>Histology</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> Serous</td><td rowspan="1" colspan="1">110</td><td rowspan="1" colspan="1">70.5%</td></tr><tr><td rowspan="1" colspan="1"> Clear cell</td><td rowspan="1" colspan="1">12</td><td rowspan="1" colspan="1">7.7%</td></tr><tr><td rowspan="1" colspan="1"> Endometrioid</td><td rowspan="1" colspan="1">21</td><td rowspan="1" colspan="1">13.5%</td></tr><tr><td rowspan="1" colspan="1"> Mucinous</td><td rowspan="1" colspan="1">13</td><td rowspan="1" colspan="1">8.3%</td></tr><tr><td rowspan="1" colspan="1"><bold>Lymph node</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> pN0/X</td><td rowspan="1" colspan="1">104</td><td rowspan="1" colspan="1">66.7%</td></tr><tr><td rowspan="1" colspan="1"> pN1</td><td rowspan="1" colspan="1">52</td><td rowspan="1" colspan="1">33.3%</td></tr><tr><td rowspan="1" colspan="1"><bold>Distant metastasis</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> pM0/X</td><td rowspan="1" colspan="1">150</td><td rowspan="1" colspan="1">96.2%</td></tr><tr><td rowspan="1" colspan="1"> pM1</td><td rowspan="1" colspan="1">6</td><td rowspan="1" colspan="1">3.8%</td></tr><tr><td rowspan="1" colspan="1"><bold>Grading</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> Low</td><td rowspan="1" colspan="1">38</td><td rowspan="1" colspan="1">25.0%</td></tr><tr><td rowspan="1" colspan="1"> High</td><td rowspan="1" colspan="1">117</td><td rowspan="1" colspan="1">75.0%</td></tr><tr><td rowspan="1" colspan="1"><bold>FIGO</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> I</td><td rowspan="1" colspan="1">35</td><td rowspan="1" colspan="1">22.4%</td></tr><tr><td rowspan="1" colspan="1"> II</td><td rowspan="1" colspan="1">10</td><td rowspan="1" colspan="1">6.4%</td></tr><tr><td rowspan="1" colspan="1"> III</td><td rowspan="1" colspan="1">103</td><td rowspan="1" colspan="1">66.0%</td></tr><tr><td rowspan="1" colspan="1"> IV</td><td rowspan="1" colspan="1">3</td><td rowspan="1" colspan="1">1.9%</td></tr><tr><td rowspan="1" colspan="1"><bold>Age</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> ≤60 years</td><td rowspan="1" colspan="1">83</td><td rowspan="1" colspan="1">53.2%</td></tr><tr><td rowspan="1" colspan="1"> >60 years</td><td rowspan="1" colspan="1">73</td><td rowspan="1" colspan="1">46.8%</td></tr></tbody></table></table-wrap></p><p>NRF2 staining in both cytoplasm and nucleus was different between the histological subtypes (<italic>p</italic>=0.001 and <italic>p</italic>=0.02, respectively) with low nuclear NRF2 expression in serous, clear-cell, and endometrioid histology and high expression in mucinous subtype. In comparison, strongest and weakest cytoplasmic NRF2 staining were found in the serous and clear-cell subtypes, respectively. Cytoplasmic NRF2 expression was significantly higher expressed in patients with low-grade histology (<italic>p</italic>=0.03) and low nuclear NRF2 expression was associated with age (<italic>p</italic>=0.045).</p><p>All 156 cases could be successfully stained for PRA (100%) and PRA expression could be detected in 63 of 156 (40%) specimens with a median (range) IRS of 0 (0,12) and mean (range) IRS of 2 (0,12) (<xref rid="F0001" ref-type="fig">Figure 1</xref>). There was a significant difference in the PRA expression comparing all histological subtypes (<italic>p</italic>=0.02) with the highest expression in the serous subtype. All other parameters like grading, FIGO, lymph node involvement (pN), and distant metastasis (pM) showed no significant differences in the PRA expression. Of note, a strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, <italic>p</italic>=0.003, <xref rid="T0002" ref-type="table">Table 2</xref> and <xref rid="F0001" ref-type="fig">Figures 1</xref> and <xref rid="F0003" ref-type="fig">3</xref>).<table-wrap id="T0002" orientation="portrait" position="float"><label>Table 2</label><caption><p>Correlation analysis</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Staining</th><th rowspan="1" colspan="1">NRF2 cytoplasm</th><th rowspan="1" colspan="1">PRA</th><th rowspan="1" colspan="1">PRB</th></tr></thead><tbody><tr><td rowspan="1" colspan="1"><bold>NRF2 cytoplasm</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> cc</td><td rowspan="1" colspan="1">1.000</td><td rowspan="1" colspan="1">0.247</td><td rowspan="1" colspan="1">0.25</td></tr><tr><td rowspan="1" colspan="1"> <italic>p</italic></td><td rowspan="1" colspan="1">.</td><td rowspan="1" colspan="1">0.003</td><td rowspan="1" colspan="1">0.003</td></tr><tr><td rowspan="1" colspan="1"> n</td><td rowspan="1" colspan="1">146</td><td rowspan="1" colspan="1">142</td><td rowspan="1" colspan="1">144</td></tr><tr><td rowspan="1" colspan="1"><bold>PRA</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> cc</td><td rowspan="1" colspan="1">0.247</td><td rowspan="1" colspan="1">1.000</td><td rowspan="1" colspan="1">0.622</td></tr><tr><td rowspan="1" colspan="1"> <italic>p</italic></td><td rowspan="1" colspan="1">0.003</td><td rowspan="1" colspan="1">.</td><td rowspan="1" colspan="1">0.0001</td></tr><tr><td rowspan="1" colspan="1"> n</td><td rowspan="1" colspan="1">142</td><td rowspan="1" colspan="1">152</td><td rowspan="1" colspan="1">152</td></tr><tr><td rowspan="1" colspan="1"><bold>PRB</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> cc</td><td rowspan="1" colspan="1">0.25</td><td rowspan="1" colspan="1">0.622</td><td rowspan="1" colspan="1">1.000</td></tr><tr><td rowspan="1" colspan="1"> <italic>p</italic></td><td rowspan="1" colspan="1">0.003</td><td rowspan="1" colspan="1">0.0001</td><td rowspan="1" colspan="1">.</td></tr><tr><td rowspan="1" colspan="1"> n</td><td rowspan="1" colspan="1">144</td><td rowspan="1" colspan="1">152</td><td rowspan="1" colspan="1">154</td></tr></tbody></table><table-wrap-foot><fn><p><bold>Notes:</bold> IR-scores of NRF2 and PRA/PRB staining were correlated to each other using Spearman’s correlation analysis.</p></fn><fn><p><bold>Abbreviations:</bold> cc, correlation coefficient, <italic>p</italic>, two-tailed significance, n, number of patients.</p></fn></table-wrap-foot></table-wrap><fig id="F0001" fig-type="figure" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Detection of NRF2 and PRA/PRB with immunohistochemistry.</p><p><bold>Notes:</bold> High cytoplasmic NRF2 staining (<bold>A</bold>) corresponds with high PRA (<bold>B</bold>) and high PRB (<bold>C</bold>) staining found in specimens from the same individual. NRF2 cytoplasmic expression correlated with PRA (cc=0.247, <italic>p</italic>=0.003) and PRB expression (cc=0.25, <italic>p</italic>=0.003). <bold>Abbreviations:</bold> cc, correlation coefficient, p = two-tailed significance.</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0002"></graphic></fig><fig id="F0003" fig-type="figure" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Correlation analysis of NRF2 and PRA/PRB.</p><p><bold>Notes:</bold> Correlation analysis of NRF2 and PRA (<bold>A</bold>)/PRB (<bold>B</bold>) in ovarian cancer tissue. A significant correlation of cytoplasmic NRF2 expression with PRA/PRB expression was noted. For better visualization, dots have been jittered.</p><p><bold>Abbreviations:</bold> r = correlation coefficient, p = two-tailed significance, n = number of patients.</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0003"></graphic></fig></p><p>PRB staining was successfully performed in all 156 cases (100%) and PRB expression was observed in 63 of 156 (40%) specimens with a median (range) IRS of 0 (0,12) and mean (range) IRS of 2 (0,12) (<xref rid="F0001" ref-type="fig">Figure 1</xref>). Parameters like histological subtypes, grading, FIGO, lymph node involvement (pN), and distant metastasis (pM) showed no significant differences in the PRB expression. Again, NRF2 cytoplasmic expression was correlated with PRB expression (cc=0.25, <italic>p</italic>=0.003, <xref rid="T0002" ref-type="table">Table 2</xref> and <xref rid="F0001" ref-type="fig">Figures 1</xref>–<xref rid="F0003" ref-type="fig">3</xref>).</p></sec><sec id="S0003-S2002"><title>High NRF2/PR expression is associated with improved overall survival</title><p>Median age of the patients was 58.7 (standard deviation [SD] 31.4) years with a range of 31–88 years. Median follow-up OS of the EOC patients was 34.4 (SD 57.8) months. Although not statistically significant, cytoplasmic NRF2 expression was associated with a longer OS (<xref rid="F0004" ref-type="fig">Figure 4</xref>, median 50.6 vs 32.5 months; <italic>p</italic>=0.1) as it was seen for PRA expression (<xref rid="F0004" ref-type="fig">Figure 4</xref>, median 63.4 vs 33.1 months; <italic>p</italic>=0.08). In addition, high PRB expression was associated with increased OS (<xref rid="F0004" ref-type="fig">Figure 4</xref>, median 80.4 vs 32.5 months; <italic>p</italic>=0.04).<fig id="F0004" fig-type="figure" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Kaplan–Meier estimates.</p><p><bold>Notes:</bold> Kaplan–Meier estimates of NRF2 expression (<bold>A</bold>), PRA expression (<bold>B</bold>), PRB expression (<bold>C</bold>) and combined NRF2 and PRA/PRB (<bold>D, E</bold>) expression were analyzed. Although not statistically significant, cytoplasmic NRF2 expression was noted with a longer overall survival (<bold>A</bold>) as it was seen for PRA expression (<bold>B</bold>). High PRB expression was associated with increased overall survival (<bold>C</bold>). Patients with combined high NRF2 expression in the cytoplasm and PRA/PRB expression had significantly increased overall survival compared with those with low cytoplasmic expression (<bold>D</bold>/<bold>E</bold>).</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0004"></graphic></fig></p><p>Due to the biological relationship between NRF2 and PRA, concurrent expression of cytoplasmic NRF2 and PRA was evaluated revealing significantly longer OS for patients expressing both, NRF2 and PRA (<xref rid="F0004" ref-type="fig">Figure 4</xref>, median 109.7 vs 30.6 months; <italic>p</italic>=0.02). The same relationship was also noted between NRF2 and PRB with improved OS for patients with the combined expression of cytoplasmic NRF2 and PRB (<xref rid="F0004" ref-type="fig">Figure 4</xref>, median 153.5 vs 30.6 months; <italic>p</italic>=0.009).</p></sec><sec id="S0003-S2003"><title>Clinical and pathological parameters are independent prognostic factors</title><p>Cancer grading, the FIGO classification, and patient’s age were independent prognostic factors in the present cohort (<xref rid="T0003" ref-type="table">Table 3</xref>). In contrast, the prognostic impact of histological subtype as well as NRF2 and PRA/PRB expression were not confirmed to be of independent significance.<table-wrap id="T0003" orientation="portrait" position="float"><label>Table 3</label><caption><p>Multivariate analysis</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Covariate</th><th rowspan="1" colspan="1">Coefficient (b<sub>i</sub>)</th><th rowspan="1" colspan="1">[HR Exp(b<sub>i</sub>)]</th><th colspan="2" rowspan="1">95% CI</th><th rowspan="1" colspan="1"><italic>p</italic>-Value</th></tr><tr><th rowspan="1" colspan="1">Lower</th><th rowspan="1" colspan="1">Upper</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Histology (serous vs other)</td><td rowspan="1" colspan="1">−0.124</td><td rowspan="1" colspan="1">0.883</td><td rowspan="1" colspan="1">0.678</td><td rowspan="1" colspan="1">1.188</td><td rowspan="1" colspan="1">0.35</td></tr><tr><td rowspan="1" colspan="1">Grade (low vs high)</td><td rowspan="1" colspan="1">0.472</td><td rowspan="1" colspan="1">1.604</td><td rowspan="1" colspan="1">1.158</td><td rowspan="1" colspan="1">2.138</td><td rowspan="1" colspan="1">0.002</td></tr><tr><td rowspan="1" colspan="1">FIGO (I, II vs III, IV)</td><td rowspan="1" colspan="1">0.679</td><td rowspan="1" colspan="1">1.972</td><td rowspan="1" colspan="1">1.550</td><td rowspan="1" colspan="1">3.096</td><td rowspan="1" colspan="1">0.000</td></tr><tr><td rowspan="1" colspan="1">Patients’ age (≤60 vs >60 years)</td><td rowspan="1" colspan="1">0.008</td><td rowspan="1" colspan="1">1.008</td><td rowspan="1" colspan="1">1.003</td><td rowspan="1" colspan="1">1.013</td><td rowspan="1" colspan="1">0.001</td></tr><tr><td rowspan="1" colspan="1">NRF2 cytoplasmic/PRA</td><td rowspan="1" colspan="1">−0.090</td><td rowspan="1" colspan="1">0.914</td><td rowspan="1" colspan="1">0.382</td><td rowspan="1" colspan="1">2.332</td><td rowspan="1" colspan="1">0.85</td></tr><tr><td rowspan="1" colspan="1">NRF2 cytoplasmic/PRB</td><td rowspan="1" colspan="1">−0.422</td><td rowspan="1" colspan="1">0.656</td><td rowspan="1" colspan="1">0.276</td><td rowspan="1" colspan="1">1.639</td><td rowspan="1" colspan="1">0.35</td></tr></tbody></table></table-wrap></p></sec><sec id="S0003-S2004"><title>Downregulation of NFE2L2 influences PGR expression confirming their genetic interaction</title><p>Following effective silencing of <italic>NFE2L2</italic> with siRNA to evaluate the impact on <italic>PGR</italic> expression (<xref rid="F0005" ref-type="fig">Figure 5</xref>), an elevated expression of <italic>PGR</italic> in the <italic>NFE2L2</italic> downregulated cancer cell line OVCAR3 was noted, although not statistically significant (<italic>p</italic>=0.41).<fig id="F0005" fig-type="figure" orientation="portrait" position="float"><label>Figure 5</label><caption><p>siRNA downregulation of <italic>NFE2L2.</italic></p><p><bold>Notes:</bold> siRNA downregulation of <italic>NFE2L2</italic> in the ovarian cancer cell line OVCAR3 (<bold>A</bold>) and the effect on <italic>PGR</italic> expression following <italic>NFE2L2</italic> downregulation (<bold>B</bold>).</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0005"></graphic></fig></p></sec></sec><sec id="S0004"><title>Discussion</title><p>The present study investigating the expression patterns of NRF2 and PRA as well as PRB demonstrates that cytoplasmic NRF2 expression is significantly correlated with the expression of both PRA and PRB and that this correlation seems to be associated with a significant impact on OS of ovarian cancer patients. Silencing of <italic>NFE2L2</italic> induced a higher mRNA expression of <italic>PGR</italic> in the <italic>NFE2L2</italic> downregulated cancer cell line OVCAR3. Therefore, these results might corroborate a possible functional interaction between NRF2 and PR which merits further investigations.</p><p>As a main cellular defense mechanism against metabolic, xenobiotic, and oxidative stress, NRF2 has been generally regarded as a tumor suppressor.<xref rid="CIT0033" ref-type="bibr">33</xref>,<xref rid="CIT0034" ref-type="bibr">34</xref> NRF2 activation avoids excessive cellular damage under abovementioned conditions.<xref rid="CIT0034" ref-type="bibr">34</xref> Thus, NRF2/Keap1 pathway is essential in cancer chemoprevention underlining NRF2/Keap1 mutations at pre-neoplastic stages in experimental models.<xref rid="CIT0035" ref-type="bibr">35</xref> In comparison, recent studies revealed that NRF2 hyperactivation may facilitate conditions favoring the survival of normal as well as malignant cells, protecting them from apoptosis following oxidative stress by chemotherapeutic agents or radiotherapy.<xref rid="CIT0036" ref-type="bibr">36</xref>,<xref rid="CIT0037" ref-type="bibr">37</xref></p><p>Hence, this potential dual role of NRF2 in cancer biology should be taken into account in interpretation of its molecular role. Studies revealed that nuclear or activated NRF2 expression is associated with upregulation of multiple target genes with negative prognostic effects leading to impaired overall as well as progression-free survival (PFS). In accordance, patients with high cytoplasmic NRF2 expression (inactive form of the transcription factor) displayed improved OS and PFS.<xref rid="CIT0014" ref-type="bibr">14</xref>,<xref rid="CIT0038" ref-type="bibr">38</xref></p><p>Progesterone plays an anti-proliferative effect via its receptor and has hereby been reported to be associated with improved OS and PFS in ovarian cancer patients.<xref rid="CIT0024" ref-type="bibr">24</xref>–<xref rid="CIT0027" ref-type="bibr">27</xref> These findings are supported by studies showing that PR mediates apoptotic cell death.<xref rid="CIT0039" ref-type="bibr">39</xref>,<xref rid="CIT0040" ref-type="bibr">40</xref> Furthermore, upregulation of Forkhead-box transcription factor (FOXO1) through progestin activated PR causes cell cycle arrest by increasing of mediators of cell senescence.<xref rid="CIT0040" ref-type="bibr">40</xref>,<xref rid="CIT0041" ref-type="bibr">41</xref> A potential interaction between NRF2 and PR is not well understood yet, but can be conceived as a hypothesis-generating approach based on the presented evidence. NRF2 activates its target gene aldo-keto reductase family 1 member C1 (AKR1C1) amongst others via an antioxidant response element (ARE) in a specific promoter region. AKR1C1 converts progesterone to its inactive form, the 20-alpha-dihydroxyprogesterone (20-alpha-OHP).<xref rid="CIT0042" ref-type="bibr">42</xref>,<xref rid="CIT0043" ref-type="bibr">43</xref> Moreover, AKR1C1 can bind to the promoter region of PR and decreases hereby receptor activity.<xref rid="CIT0044" ref-type="bibr">44</xref> In this study, silencing of <italic>NFE2L2</italic> induced a higher mRNA expression of <italic>PGR</italic> supporting this data. In endometrial cancer patients, concurrent NRF2/AKR1C1 overexpression was proposed to be part of the molecular mechanisms underlying progestin resistance.<xref rid="CIT0045" ref-type="bibr">45</xref> Accordingly, increased expression of AKR1C1 is associated with the development of platinum resistance in human ovarian carcinoma cells as well as colon carcinoma cells.<xref rid="CIT0046" ref-type="bibr">46</xref>,<xref rid="CIT0047" ref-type="bibr">47</xref> In contrast, progesterone facilitates the toxicity of cisplatin in ovarian cancer cells and a preclinical murine xenograft model.<xref rid="CIT0048" ref-type="bibr">48</xref> Taken together, the interaction of NRF2 and PR might represent a potential pathway significantly influencing platinum response being mediated by AKR1C1 in ovarian cancer which should be followed in future studies. NRF2/AKR1C1 expression can be downregulated by metformin treatment as described in endometrial and lung cancer cells.<xref rid="CIT0045" ref-type="bibr">45</xref>,<xref rid="CIT0049" ref-type="bibr">49</xref>,<xref rid="CIT0050" ref-type="bibr">50</xref> Interestingly, recent studies show that metformin, usually applied in diabetic patients, prevents tumor growth, induces apoptosis and increases sensitivity to chemotherapy in ovarian cancer cells.<xref rid="CIT0051" ref-type="bibr">51</xref>–<xref rid="CIT0057" ref-type="bibr">57</xref> Mechanisms underlying these cellular effects include suppression of cancer stem cells, inhibition of epithelial-to-mesenchymal transition and interference with neoplastic cell metabolism.<xref rid="CIT0058" ref-type="bibr">58</xref>–<xref rid="CIT0062" ref-type="bibr">62</xref> Following promising data of epidemiological studies showing a favorable effect of metformin on ovarian cancer incidence and survival, it was proposed that metformin should be followed as an additional approach in ovarian cancer treatment.<xref rid="CIT0063" ref-type="bibr">63</xref>–<xref rid="CIT0065" ref-type="bibr">65</xref> As metformin treatment is associated with an increased PR expression, these results further support future investigations of the above-described relationships in the NRF2/AKR1C1/PR pathway and their impact on ovarian cancer biology and the clinical behavior.</p></sec><sec id="S0005"><title>Conclusion</title><p>In summary, based on the results of the present study, we hypothesize that the interplay between NRF2/AKR1C1/PR might serve as an important pathway with significant impact on ovarian carcinogenesis elucidating additional therapeutic perspectives (<xref rid="F0006" ref-type="fig">Figure 6</xref>). With the rationale described earlier, metformin might have favorable effects on ovarian cancer biology and open new approaches to overcome platinum resistance which needs to be proved in future studies.<fig id="F0006" fig-type="figure" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Summary of the hypothesized interaction within the NRF2/AKR1C1/PR pathway.</p><p><bold>Notes:</bold> Activated NRF2 (high nuclear, low cytoplasmic expression) activates aldo-keto reductase family 1 member C1 (AKR1C1) via an antioxidant response element (ARE). AKR1C1 converts progesterone to its inactive form, the 20-alpha-dihydroxyprogesterone, and decreases PR receptor activity with consecutive platinum resistance. Metformin treatment counteracts this pathway, which may reverse the effects and consecutively lead to platinum re-sensitization.</p></caption><graphic content-type="print-only" xlink:href="CMAR-11-7673-g0006"></graphic></fig></p></sec></body><back><ack><title>Acknowledgments</title><p>The authors are grateful to Mrs Martina Rahmeh and Mrs Christina Kuhn for excellent technical assistance. This work has been funded by the “Monika Kutzner” foundation and the “Brigitte & Dr. Konstanze Wegener” foundation.</p></ack><sec id="S0006" sec-type="COI-statement"><title>Disclosure</title><p>Bastian Czogalla has received a research grant from the “Monika Kutzner” foundation and “Brigitte & Dr. Konstanze Wegener” foundation. Anna Hester has received a research grant from the “Walter Schulz” foundation and advisory board, speech honoraria and travel expenses from Roche and Pfizer. Thomas Kolben´s relative is employed at Roche AG. Research support, advisory board, honoraria, and travel expenses from AstraZeneca, Clovis, Medac, MSD, Novartis, PharmaMar, Roche, Sensor Kinesis, Tesaro, Teva have been received by Sven Mahner and from AstraZeneca, Medac, PharmaMar, Roche, Tesaro by Fabian Trillsch. 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