Supplementary Table 4 from Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

Wik, Elisabeth; Ræder, Maria B.; Krakstad, Camilla; Trovik, Jone; Birkeland, Even; Hoivik, Erling A.; Mjos, Siv; Werner, Henrica M.J.; Mannelqvist, Monica; Stefansson, Ingunn M.; Oyan, Anne M.; Kalland, Karl H.; Akslen, Lars A.; Salvesen, Helga B.

doi:10.1158/1078-0432.22448196.v1

Supplementary Table 4 from Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

journal contribution

posted on 2023-03-31, 17:22 authored by Elisabeth Wik, Maria B. Ræder, Camilla Krakstad, Jone Trovik, Even Birkeland, Erling A. Hoivik, Siv Mjos, Henrica M.J. Werner, Monica Mannelqvist, Ingunn M. Stefansson, Anne M. Oyan, Karl H. Kalland, Lars A. Akslen, Helga B. Salvesen

PDF file - 68 KB, Subset of endometrioid cases, retrospective population based series. Cox' proportional hazard regression model used to estimate the prognostic value of ER� in relation to traditional prognostic markers in endometrial carcinoma.

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ARTICLE ABSTRACT

Purpose: We hypothesized that estrogen receptor-α (ER-α) 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 immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.Results: ER-α immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-α 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 ER-α and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-α–negative tumors. Low ER-α was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-α was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.Conclusion: Lack of ER-α in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-α's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-α–negative endometrial carcinomas. Clin Cancer Res; 19(5); 1094–105. ©2012 AACR.