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Estrogen receptors (ER) and nuclear factor-κB (NF-κB) are known to play important roles in breast cancer, but these factors are generally thought to repress each other's activity. However, we have recently found that ER and NF-κB can also act together in a positive manner to synergistically increase gene transcription. To examine the extent of cross-talk between ER and NF-κB, a microarray study was conducted in which MCF-7 breast cancer cells were treated with 17β-estradiol (E₂), tumor necrosis factor α (TNFα), or both. Follow-up studies with an ER antagonist and NF-κB inhibitors show that cross-talk between E₂ and TNFα is mediated by these two factors. We find that although transrepression between ER and NF-κB does occur, positive cross-talk is more prominent with three gene-specific patterns of regulation: (a) TNFα enhances E₂ action on ∼30% of E₂-upregulated genes; (b) E₂ enhances TNFα …