title: ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer.
abstract: 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.
authors.affiliation: Department of Gastrointestinal Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Shi
authors.affiliation: Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital, Tianjin 300192, China.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.|2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Medical College of Nankai University, Tianjin 300071, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013629:Tamoxifen / Q000494:pharmacology; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D013629:Tamoxifen