Positive Cross-Talk between Estrogen Receptor and NF-κB in Breast Cancer

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 17βestradiol (E2), tumor necrosis factor α (TNFα), or both. Followup 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 activity on ∼15% of TNFα-upregulated genes; and (c) E2 + TNFα causes a more than additive upregulation of ∼60 genes. Consistent with their prosurvival roles, ER and NF-κB and their target gene, BIRC3, are involved in protecting breast cancer cells against apoptosis. Furthermore, genes positively regulated by E2 + TNFα are clinically relevant because they are enriched in luminal B breast tumors and their expression profiles can distinguish a cohort of patients with poor outcome following endocrine treatment. Taken together, our findings suggest that positive cross-talk between ER and NF-κB is more extensive than anticipated and that these factors may act together to promote survival of breast cancer cells and progression to a more aggressive phenotype. [Cancer Res 2009;69(23):8918–25]