ERalpha as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells.
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.
Cardamone
Maria Dafne
MD
Department of Medicine, Howard Hughes Medical Institute, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
Bardella
Chiara
C
Gutierrez
Arantxa
A
Di Croce
Luciano
L
Rosenfeld
Michael G
MG
Di Renzo
Maria Flavia
MF
De Bortoli
Michele
M
D000595:Amino Acid Sequence; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands