title: ERalpha as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Maria Dafne
authors.initials: MD
authors.lastname: Cardamone
authors.forename: Chiara
authors.initials: C
authors.lastname: Bardella
authors.forename: Arantxa
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
authors.forename: Michele
authors.initials: M
authors.lastname: De Bortoli
mesh_terms: 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
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands