Estrogen induces estrogen-related receptor alpha gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells.
Estrogen-related receptor alpha (ERRalpha), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ERalpha and ERbeta). The ERRalpha 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 ERRalpha gene expression. ERRalpha was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ERalpha. The contribution of ERRalpha in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERRalpha gene expression and chromatin structural changes under the influence of 17beta-estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERRalpha 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 17beta-estradiol induces ERRalpha gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERRalpha and AP1 bind and ERalpha is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines.
Hu
Peng
P
Gene Regulation Section, Laboratory of Reproductive and Developmental Toxicology and Chromatin and Gene Expression Section, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Kinyamu
H Karimi
HK
Wang
Liangli
L
Martin
Jessica
J
Archer
Trevor K
TK
Teng
Christina
C
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008836:Micrococcal Nuclease / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D009707:Nucleosomes / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D000097983:ERRalpha Estrogen-Related Receptor
D002843:Chromatin; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D000077267:Fulvestrant; D008836:Micrococcal Nuclease; D009707:Nucleosomes; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor