Estrogen-mediated down-regulation of E-cadherin in breast cancer cells.
E-cadherin is an important mediator of cell-cell interactions, and has been shown to play a crucial role in breast tumor suppression. Its inactivation occurs through instability at its chromosomal locus and mutations, but also through epigenetic mechanisms such as promoter hypermethylation and transcriptional silencing. We show here that the potent mitogen estrogen causes down-regulation of E-cadherin levels in both normal and tumorigenic breast epithelial cells, and that this down-regulation is reversed by antiestrogens. The reduction in E-cadherin levels is via a decrease in promoter activity and subsequent mRNA levels. Chromatin immunoprecipitation assays revealed that estrogen receptor and corepressors were bound to the E-cadherin promoter, and that overexpression of corepressors such as scaffold attachment factor B resulted in enhanced repression of E-cadherin. We propose that estrogen-mediated down-regulation of E-cadherin is a novel way of reducing E-cadherin levels in estrogen receptor-positive breast cancer.
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015820:Cadherins; D016895:Culture Media, Serum-Free; D020847:Estrogen Receptor Modulators; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol