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Elucidation of Chromatin Remodeling Machinery Involved in Regulation of Estrogen Receptor Alpha Expression in Human Breast Cancer Cells

机译:阐明染色质重塑机制参与调节人乳腺癌细胞中雌激素受体α的表达

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Breast tumors expressing estrogen receptor alpha (ER) respond well to therapeutic strategies using SERMs (selective estrogen receptor modulators) such as tamoxifen. However, about thirty percent of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER negative breast cancer cells with demethylating agents (5-aza-2 deoxycytidine or 5-aza-dC) and histone deacetylase inhibitors (trichostatin A or TSA) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with TSA and 5-aza-dC, the formerly unresponsive ER negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor (NCoR) - histone deacetylase 3 (HDAC3) complex followed by NuRD (nucleosome remodeling and histone deacetylation) complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed towards epigenetic mechanisms in the prevention or treatment of breast cancer.

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