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

摘要

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.