ERα as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells
Open Access
- 5 May 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (18), 7420-7425
- https://doi.org/10.1073/pnas.0903033106
Abstract
Estrogen receptor α (ERα) and E-cadherin are primary markers of luminal epithelial breast cancer cells with E-cadherin being a main caretaker of the epithelial phenotype. E-cadherin repression is needed for cancer cells to acquire motile and invasive properties, and it is known that in ER-positive breast cancer cells, estrogen down-regulate E-cadherin gene transcription. We report here that ERα is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ERα in E-cadherin transcription. Indeed, our data reveal that activation by unliganded ERα and repression by estrogen-activated ERα require direct binding to a half-estrogen response element within the E-cadherin promoter and exchange from associated coactivators to corepressors. Therefore, these results suggest a pivotal role for unliganded ERα in controlling a fundamental caretaker of the epithelial phenotype in breast cancer cells. Here, we show that ERα-positive breast cancer T47D cells transduced with the sfRON kinase undergo a full epithelial–mesenchymal conversion and lose E-cadherin and ERα expression. Our data show that, although the E-cadherin gene becomes hypermethylated and heterochromatic, kinase inhibitors can restore E-cadherin expression, together with an epithelial morphology in an ERα-dependent fashion. Similarly, transfection of ERα, in the absence of ligands, was sufficient to restore E-cadherin transcription in both sfRON-T47D and other ERα-, E-cadherin-negative cells. Therefore, our results suggest a novel role for the ERα that plays the dual role of ligand-independent activator and ligand-dependent repressor of E-cadherin in breast cancer cells.Keywords
This publication has 40 references indexed in Scilit:
- Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signaturesBreast Cancer Research, 2008
- Estrogen Receptor-α Overexpression Suppresses 17β-Estradiol-Mediated Vascular Endothelial Growth Factor Expression and Activation of Survival KinasesEndocrinology, 2008
- The Transcription Factor Snail Mediates Epithelial to Mesenchymal Transitions by Repression of Estrogen Receptor-αMolecular Endocrinology, 2007
- Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherinCell Research, 2007
- Sensitive ChIP-DSL technology reveals an extensive estrogen receptor α-binding program on human gene promotersProceedings of the National Academy of Sciences of the United States of America, 2007
- Genome-wide analysis of estrogen receptor binding sitesNature Genetics, 2006
- Complex networks orchestrate epithelial–mesenchymal transitionsNature Reviews Molecular Cell Biology, 2006
- Profiling of Estrogen Up- and Down-Regulated Gene Expression in Human Breast Cancer Cells: Insights into Gene Networks and Pathways Underlying Estrogenic Control of Proliferation and Cell PhenotypeEndocrinology, 2003
- Breast cancer classification and prognosis based on gene expression profiles from a population-based studyProceedings of the National Academy of Sciences of the United States of America, 2003
- Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implicationsProceedings of the National Academy of Sciences of the United States of America, 2001