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