Differential regulation of estrogen receptor alpha expression in breast cancer cells by metastasis-associated protein 1.
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Kang HJ, Lee MH, Kang HL, Kim SH, Ahn JR, Na H, Na TY, Kim YN, Seong JK, Lee MO
Differential regulation of estrogen receptor alpha expression in breast cancer cells by metastasis-associated protein 1.
Cancer Res. 2014 Mar 1;74(5):1484-94. doi: 10.1158/0008-5472.CAN-13-2020. Epub 2014 Jan 10.
- PubMed ID
- 24413532 [ View in PubMed]
- 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 alpha (ERalpha), its involvement in the epigenetic control of transcription of the ERalpha gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERalpha in ERalpha-positive cells but increased it in ERalpha-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-2gamma (TFAP2C) and the IFN-gamma-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERalpha mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERalpha. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERalpha. 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.