Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to estrogen receptor-α responsive promoters

In breast cancer and normal estrogen target tissues, estrogen receptor-alpha (ER alpha) signaling results in the establishment of spatiotemporal patterns of gene expression. Whereas primary target gene regulation by ER alpha involves recruitment of coregulatory proteins, co-activators, or corepressors, activation of these downstream promoters by receptor signaling may also involve partnership of ER alpha with other transcription factors. By using an integrated, genome-wide approach that involves ChIP-chip and computational modeling, we uncovered 13 ER alpha-responsive promoters containing both ER alpha and c-MYC binding elements located within close proximity (13-214 bp) to each other. Estrogen stimulation enhanced the c-MYC-ER alpha interaction and facilitated the association of ER alpha, c-MYC, and the coactivator TRRAP with these estrogen-responsive promoters, resulting in chromatin remodeling and increased transcription. These results suggest that ER alpha and c-MYC physically interact to stabilize the ER alpha-coactivator complex, thereby permitting other signal transduction pathways to fine-tune estrogen-mediated signaling networks.