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

• Published in: Cell death & disease Vol. 8; no. 4; p. e2732
• Main Authors: Zhang, Jianbo, Zhou, Chen, Jiang, Huimin, Liang, Lin, Shi, Wen, Zhang, Quansheng, Sun, Peiqing, Xiang, Rong, Wang, Yue, Yang, Shuang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/106; 13/109; 13/51; 13/89; 631/67/1059/2326; 631/67/1347; 631/80/458/1648; 631/80/86; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Culture; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Drug Resistance, Neoplasm; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Immunology; Life Sciences; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Original; original-article; Promoter Regions, Genetic; Tamoxifen - pharmacology; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.154

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.