TY - JOUR
T1 - ERα as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells
AU - Cardamone, Maria Dafne
AU - Bardella, Chiara
AU - Gutierrez, Arantxa
AU - Croce, Luciano Di
AU - Rosenfeld, Michael G.
AU - Renzo, Maria Flavia Di
AU - De Bortoli, Michele
PY - 2009/5/5
Y1 - 2009/5/5
N2 - 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.
AB - 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.
KW - E-cadherin
KW - Epithelial to mesenchymal transition
KW - Estrogen
KW - Invasion
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U2 - 10.1073/pnas.0903033106
DO - 10.1073/pnas.0903033106
M3 - Article
C2 - 19383788
AN - SCOPUS:66149102496
VL - 106
SP - 7420
EP - 7425
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 18
ER -