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

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.