ERα as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells

Maria Dafne Cardamone, Chiara Bardella, Arantxa Gutierrez, Luciano Di Croce, Michael G. Rosenfeld, Maria Flavia Di Renzo, Michele De Bortoli

Research output: Contribution to journalArticle

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 ERa 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 hy- permethylated 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.

Original languageEnglish
Pages (from-to)7420-7425
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number18
DOIs
Publication statusPublished - May 5 2009

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Keywords

  • E-cadherin
  • Epithelial to mesenchymal transition
  • Estrogen
  • Invasion

ASJC Scopus subject areas

  • General

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