Estrogen induces estrogen-related receptor α gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells

Estrogen-related receptor alpha(ERR alpha), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ER alpha and ER beta). The ERR alpha gene is estrogen-responsive in several mouse tissues and cell lines, and a multiple hormone-response element (MHRE) in the promoter is an important regulatory region for estrogen- induced ERR alpha gene expression. ERR alpha was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ER alpha. The contribution of ERR alpha in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERR alpha gene expression and chromatin structural changes under the influence of 17 beta- estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERR alpha promoter around the MHRE region and found that the MHRE resides within a single nucleosome. Local chromatin structure of the MHRE exhibited increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation upon estrogen treatment. Interestingly, estrogen- induced chromatin structural changes could be repressed by estrogen antagonist ICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells. We demonstrated, using chromatin immunoprecipitation assays, that 17 beta- estradiol induces ERR alpha gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERR alpha and AP1 bind and ER alpha is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines.