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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 18; pp. 7420 - 7425
• Main Authors: Cardamone, Maria Dafne, Bardella, Chiara, Gutierrez, Arantxa, Di Croce, Luciano, Rosenfeld, Michael G, Di Renzo, Maria Flavia, De Bortoli, Michele
• Format: Journal Article
• Language: English
• Published: United States 05-05-2009
• Subjects: Amino Acid Sequence; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - genetics; Cell Line, Tumor; Epithelial Cells - metabolism; Epithelial Cells - pathology; Estrogen Receptor alpha - metabolism; Gene Expression Regulation, Neoplastic; Humans; Ligands; Molecular Sequence Data; Promoter Regions, Genetic; Transcription, Genetic
• ISSN: 1091-6490
• DOI: 10.1073/pnas.0903033106

Estrogen receptor alpha (ERalpha) 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 ERalpha is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ERalpha in E-cadherin transcription. Indeed, our data reveal that activation by unliganded ERalpha and repression by estrogen-activated ERalpha 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 ERalpha in controlling a fundamental caretaker of the epithelial phenotype in breast cancer cells. Here, we show that ERalpha-positive breast cancer T47D cells transduced with the sfRON kinase undergo a full epithelial-mesenchymal conversion and lose E-cadherin and ERalpha 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 ERalpha-dependent fashion. Similarly, transfection of ERalpha, in the absence of ligands, was sufficient to restore E-cadherin transcription in both sfRON-T47D and other ERalpha-, E-cadherin-negative cells. Therefore, our results suggest a novel role for the ERalpha that plays the dual role of ligand-independent activator and ligand-dependent repressor of E-cadherin in breast cancer cells.