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

Abstract

Purpose: We hypothesized that estrogen receptor-a (ER-a) 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 ¼ 76) and three independent validation cohorts (n ¼ 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-a immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-a negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-b signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-a 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-a-negative tumors. Low ER-a was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-a was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.Conclusion: Lack of ER-a in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-a's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-a-negative endometrial carcinomas.

A Novel Wnt Regulatory Axis in Endometrioid Endometrial Cancer

“…no. G4112F), according to the manufacturer's instructions (www.agilent.com) and described earlier (37). Arrays were scanned using the Agilent Microarray Scanner Bundle.…”

Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells

“…A role for E2 in inhibiting EMT in humans was suggested in a study which found that reduced expression of ESR1 was associated with increased expression of genes involved in EMT in endometrial carcinoma samples [47]. Further, EMT is a target for sex hormones in cell types such as breast and prostate cancer cells where E2 signaling maintains an epithelial phenotype and suppresses EMT [48–51].…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[61][62][63][64][65][66] The association between EMT and PI3K activation has also been reported in ERα-negative endometrial carcinomas. [67] Twist overexpression has also been correlated with the induction of tumor cell invasion in GBM. [68] However, these malignancies usually do not metastasize out of the CNS, mainly due to their rapid relapse rate and poor prognosis.…”