title: δEF1 down-regulates ER-α expression and confers tamoxifen resistance in breast cancer.
abstract: Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-α level is considered a primary mechanism. Understanding how ER-α expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of δEF1 is up-regulated by 17β-estradiol (E2) in MCF-7 cells in an ER-α-dependent manner, through either PI3K or NF-κB pathway. Ectopic expression of δEF1 in turn repressed ER-α transcription by binding to the E(2)-box on the ER-α promoter. At the tissue level of breast cancer, there is a strong and inverse correlation between the expression levels of δEF1 and ER-α. In MCF-7 cells, an elevated expression of δEF1 made the cells less sensitive to tamoxifen treatment, whereas overexpression of ER-α compromised the effects of δEF1 and restored the sensitivity. Also, depletion of δEF1 by RNA interference in MDA-MB-231 cells restored the expression of ER-α and tamoxifen sensitivity. In conclusion, we have identified an important role of δEF1 in the development of tamoxifen resistance in breast cancer. Inhibiting δEF1 to restore ER-α expression might represent a potential therapeutic strategy for overcoming endocrine resistance in breast cancer.
authors.affiliation: Medical College of Nankai University, Tianjin, China.
authors.forename: Shaocong
authors.initials: S
authors.lastname: Guo
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Tong
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Tianhui
authors.initials: T
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D018398:Homeodomain Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D013629:Tamoxifen; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C506487:ESR1 protein, human; C486307:ZEB1 protein, human