Genomic structure of the promoters of the human estrogen receptor-alpha gene demonstrate changes in chromatin structure induced by AP2 gamma

Expression of human estrogen receptor-alpha (ER alpha) involves the activit y from several promoters that give rise to alternate untranslated 5' exons, However, the genomic locations of the alternate 5' exons have not been rep orted previously, We have developed a contig map of the human ER alpha gene that includes all of the known alternate 5' exons, By using S1 nuclease an d 5'-rapid amplification of cDNA ends, the cap sites for the alternate ER a lpha transcripts E and H were identified. DNase I-hypersensitive sites spec ific to ER alpha -positive cells were associated with each of the cap sites . A DNase I-hypersensitive site, HS1, was localized to binding sites for AP 2 in the untranslated region of exon 1 and was invariably present in the ch romatin structure of ER alpha -positive cells, Overexpression of AP2 gamma in human mammary epithelial cells generated the HS1-hypersensitive site. Th e ER alpha promoter was induced by AP2 gamma in mammary epithelial cells, a nd trans-activation was dependent upon the region of the promoter containin g the HS1 site. These results demonstrate that AP2 gamma trans-activates th e ER alpha gene in hormone-responsive tumors by Inducing changes in the chr omatin structure of the ER alpha promoter. These data are further evidence for a critical role for AP2 in the oncogenesis of hormone-responsive breast cancers.