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

作者：Cardamone Maria Dafne; Bardella Chiara; Gutierrez Arantxa; Di Croce Luciano; Rosenfeld Michael G^*; Flavia Di Renzo Maria; De Bortoli Michele

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(18): 7420-7425.

DOI：10.1073/pnas.0903033106

• E-cadherin
• epithelial to mesenchymal transition
• estrogen
• invasion

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

• 出版日期2009-5-5