title: Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
abstract: Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor α (ERα), its involvement in the epigenetic control of transcription of the ERα gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERα in ERα-positive cells but increased it in ERα-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2γ (TFAP2C) and the IFN-γ-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERα mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERα. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERα. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that the MTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer.
authors.affiliation: Authors' Affiliations: College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences; and College of Veterinary Medicine, BK21 Plus Program for Veterinary Science, Seoul National University, Seoul, Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.forename: Hae-Lim
authors.initials: HL
authors.lastname: Kang
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung-Ranh
authors.initials: JR
authors.lastname: Ahn
authors.forename: Hyelin
authors.initials: H
authors.lastname: Na
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.forename: Yo Na
authors.initials: YN
authors.lastname: Kim
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators; D050656:Transcription Factor AP-2 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C089320:MTA1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C493679:TFAP2C protein, human; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D013629:Tamoxifen; C076700:IFI16 protein, human; D006655:Histone Deacetylases