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

Estrogen receptors (ER) and nuclear factor-kappa B (NF-kappa B) 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-kappa B can also act together in a positive manner to synergistically increase gene transcription. To examine the extent of cross-talk between ER and NF-kappa B, a microarray study was conducted in which MCF-7 breast cancer cells were treated with 17 beta-estradiol (E-2), tumor necrosis factor alpha (TNF alpha), or both. Followup studies with an ER antagonist and NF-kappa B inhibitors show that cross-talk between E-2 and TNF alpha is mediated by these two factors. We find that although transrepression between ER and NF-kappa B does occur, positive cross-talk is more prominent with three gene-specific patterns of regulation: (a) TNF alpha enhances E-2 action on similar to 30% of E-2-upregulated genes; (b) E-2 enhances TNF alpha activity on similar to 15% of TNF alpha-upregulated genes; and (c) E-2 + TNF alpha causes a more than additive upregulation of similar to 60 genes. Consistent with their prosurvival roles, ER and NF-kappa B and their target gene, BLRC3, are involved in protecting breast cancer cells against apoptosis. Furthermore, genes positively regulated by E2 + TNFa 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-kappa B 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]