Genomic structure of the promoters of the human estrogen receptor-α gene demonstrate changes in chromatin structure induced by AP2γ

Expression of human estrogen receptor-alpha (ER alpha) involves the activity from several promoters that give rise to alternate untranslated 5' exons, However, the genomic locations of the alternate 5' exons have not been reported 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 and 5'-rapid amplification of cDNA ends, the cap sites for the alternate ER alpha transcripts E and H were identified. DNase I-hypersensitive sites specific 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 AP2 in the untranslated region of exon 1 and was invariably present in the chromatin structure of ER alpha -positive cells, Overexpression of AP2 gamma in human mammary epithelial cells generated the HS1-hypersensitive site. The ER alpha promoter was induced by AP2 gamma in mammary epithelial cells, and trans-activation was dependent upon the region of the promoter containing the HS1 site. These results demonstrate that AP2 gamma trans-activates the ER alpha gene in hormone-responsive tumors by Inducing changes in the chromatin 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.