Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma
- 1 March 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (5), 1094-1105
- https://doi.org/10.1158/1078-0432.ccr-12-3039
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.Keywords
Other Versions
This publication has 52 references indexed in Scilit:
- Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials GroupJournal of Clinical Oncology, 2011
- Gene Expression Patterns Related to Vascular Invasion and Aggressive Features in Endometrial CancerThe American Journal of Pathology, 2011
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- The basics of epithelial-mesenchymal transitionJCI Insight, 2009
- Biomarkers for epithelial-mesenchymal transitionsJCI Insight, 2009
- Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activationProceedings of the National Academy of Sciences of the United States of America, 2009
- Bench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesisSeminars in Cancer Biology, 2008
- Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activityProceedings of the National Academy of Sciences of the United States of America, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001