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Lack of Estrogen Receptor Α Is Associated with Epithelial-Mesenchymal

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Lack of Estrogen Receptor Α Is Associated with Epithelial-Mesenchymal Author Manuscript Published OnlineFirst on January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-3039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma Lack of Estrogen receptor α is associated with epithelial-mesenchymal transition and PI3Kinase alterations in endometrial carcinoma. Elisabeth Wik1,2, Maria B. Ræder 1,2, Camilla Krakstad1,2, Jone Trovik1,2, Even Birkeland1,2, Erling A. Hoivik1,2, Siv Mjos2, Henrica M.J. Werner1,2, Monica Mannelqvist3, Ingunn M. Stefansson3,4, Anne M. Oyan5,6, Karl H. Kalland5,6, Lars A. Akslen3,4, Helga B. Salvesen1,2 1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway, 2Department of Clinical Medicine, University of Bergen, Norway 3The Gade Institute, Section for Pathology, University of Bergen, Norway 4Department of Pathology, Haukeland University Hospital, Bergen, Norway, 5 The Gade Institute, Section for Microbiology, University of Bergen, Norway 6Department of Microbiology and Immunology, Haukeland University Hospital Running title: Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma Keywords: Endometrial carcinoma, estrogen receptor, expression analyses, epithelial- mesenchymal transition, PI3Kinase Address for correspondence: Helga B. Salvesen MD, PhD or Elisabeth Wik, MD Department of Clinical Medicine, Section for Gynecology and Obstetrics University of Bergen Haukeland University Hospital, 5021 Bergen, Norway Telephone: +47 55 97 42 00 Fax: +47 55 97 49 68 E-mail addresses: [email protected] or [email protected] 1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-3039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma Potential conflicts of interest: None of the authors indicated potential conflicts of interest. Manuscript content: 4417 words, 3 figures, 3 tables, 2 supplementary figures, 5 supplementary tables. Translational Relevance Estrogen receptor α is shown to be a strong prognostic marker and potentially predictive for response to hormonal treatment in endometrial carcinoma, although, contrasting breast cancer, not yet systematically implemented for tailoring therapy to endometrial cancer patients. In one investigation series and three independent validation sets (in total 628 patients), we identify and validate an association between ERα negative endometrial carcinomas and markers for epithelial-mesenchymal transition. Drug signature analyses suggest testing of PI3K/mTOR inhibitors in ERα negative tumors in particular. Subsequently we also find ERα negative tumors to be associated with several potential measures for PI3Kinase pathways activation. This study confirms ERα as a strong and robust prognostic marker in endometrial carcinoma and provides a rationale for clinical trials exploring the potential of ERα as predictive marker for response to inhibitors of the PI3Kinase pathway and epithelial-mesenchymal transition. 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-3039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma ABSTRACT Lack of Estrogen receptor α is associated with epithelial-mesenchymal transition and PI3Kinase alterations in endometrial carcinoma. Elisabeth Wik1,2, Maria B. Ræder 1,2, Camilla Krakstad1,2, Jone Trovik1,2, Even Birkeland1,2, Erling A. Hoivik1,2, Siv Mjos2, Henrica M.J. Werner1,2, Monica Mannelqvist3, Ingunn M. Stefansson3,4, Anne M. Oyan5,6, Karl H. Kalland5,6, Lars A. Akslen3,4, Helga B. Salvesen1,2 Purpose: We hypothesized that ERα status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy. Experimental design: Endometrial carcinoma samples in a primary investigation cohort (n=76) and three independent validation cohorts (n=155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by IHC, DNA oligonucleotide microarray, qPCR, SNP array and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up. Results: ERα immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P< 0.001). ERα negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog- and TGF-β signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ERα and EMT was validated in three independent data sets. Furthermore, PI3Kinase- and mTOR inhibitors were amongst the top ranked drug signatures negatively correlated with the ERα negative tumors. Low ERα was significantly associated with PIK3CA amplifications but not mutations. Also, low ERα was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature. 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-3039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma Conclusion: Lack of ERα in endometrial cancer is associated with epithelial-mesenchymal transition and reduced survival. We present a rationale for investigating ERα’s potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ERα negative endometrial carcinomas. INTRODUCTION Endometrial cancer is the most common gynecologic malignancy in developed countries and accounts yearly for 50 000 deaths worldwide (1). Although three quarters of these cancers are treated at an early stage, 15-20% recur (2). The most common basis for determining risk of recurrent disease is the categorization into type I and II endometrial carcinoma (3). Type I tumors are most frequent, characterized by endometrioid histology, low histologic grade, low FIGO stage and favorable prognosis. In contrast, type II tumors are characterized by non- endometrioid histology, high histologic grade and stage, and a tendency to recur, even when treated at early stage (4). However, the prognostic value of this distinction is limited, as up to 20% of type I cancers recur, while half of type II tumors do not (4). The molecular basis for type I and II cancers is only partially understood. Hyperestrogenic risk factors and positivity for estrogen receptor α (ERα) are common in type I in contrast to type II cancers, and ERα status is reported to be a prognostic marker in endometrial cancer (5, 6). Contrasting breast cancer treatment, hormone receptor status in endometrial cancer has not been clinically implemented in a systematic manner to tailor hormonal therapy (7, 8) or other targeted treatments, e.g. PI3K, mTOR or VEGF-A inhibitors (4). Epithelial-mesenchymal transition (EMT) enables epithelial cells to become more like mesenchymal cells with increased motility and the ability to invade locally, intravasate, 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-3039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Low ERα associates with EMT and PI3Kinase alterations in endometrial carcinoma circulate, extravasate and resist apoptosis (9-11). Markers of EMT are known to be associated with more aggressive tumors in different organs (12, 13). In endometrial carcinomas, alterations of EMT-related markers like E-cadherin, P-cadherin, α- and β-catenin, have been associated with metastatic disease and reduced survival (14-16). The EMT process is suggested to be a potential target for new cancer therapies (17, 18). Importantly, data linking EMT to drug resistance have been reported, indicating that EMT targeting may be relevant for cancer treatment (18). In the present study, we hypothesized that ERα negative endometrial carcinomas are associated with an aggressive clinico-pathologic phenotype and are likely to be distinguished from ERα positive tumors by underlying genetic alterations and differences in gene expression, related to key processes in cancer development and progression. Based on data from four independent patient series, we report for the first time that ERα negative endometrial carcinomas are associated with increased epithelial-mesenchymal transition. Also, inhibitors of the PI3Kinase/mTOR pathways are suggested as relevant for the treatment of ERα negative endometrial cancers in particular. PATIENTS AND METHODS Patients and follow-up Four independent endometrial carcinoma patient cohorts (including both endometrioid and non-endometrioid histologic subtypes) were studied to explore the associations between hormone receptor
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