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Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor- α  (ER- α ) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER- α  downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER- α  deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER- α  transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER- α  promoter, leading to DNA hypermethylation and the silencing of ER- α . Thus, ectopic ZEB1 downregulates ER- α  expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER- α  promoter demethylation, restores ER- α  expression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER- α  protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER- α  promoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapy  in vivo . Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer.

ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer