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

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Endometrial carcinoma samples in a primary investigation cohort (<i>n</i> = 76) and three independent validation cohorts (<i>n</i> = 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.</p><p><b>Results:</b> ER-α immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (<i>ESR1</i>) and patient survival (both <i>P</i> < 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.</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 19(5); 1094–105. ©2012 AACR</i>.</p></div>