Positive Crosstalk between Estrogen Receptor and NFκB in Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 23; pp. 8918 - 8925
• Main Authors: Frasor, Jonna, Weaver, Aisha, Pradhan, Madhumita, Dai, Yang, Miller, Lance D., Lin, Chin-Yo, Stanculescu, Adina
• Format: Journal Article
• Language: English
• Published: 17.11.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2608

Estrogen receptors (ER) and NFκB are known to play important roles in breast cancer but these factors are generally thought to repress each others’ activity. However, we have recently found that ER and NFκB can also act together in a positive manner to synergistically increase gene transcription. To examine the extent of crosstalk between ER and NFκB, a microarray study was conducted in which MCF-7 breast cancer cells were treated with 17β-estradiol (E2), TNFα, or both. Follow-up studies with an ER antagonist and NFκB inhibitors demonstrate that crosstalk between E2 and TNFα is mediated by these two factors. We find that although transrepression between ER and NFκB does occur, positive crosstalk is more prominent with three gene-specific patterns of regulation: 1) TNFα enhances E2 action on ~30% of E2 up-regulated genes, 2) E2 enhances TNFα activity on ~15% of TNFα up-regulated genes, and 3) E2+TNFα causes a more than additive up-regulation of ~60 genes. Consistent with their prosurvival roles, ER and NFκB, and their target gene BIRC3, are involved in protecting breast cancer cells against apoptosis. Furthermore, genes positively regulated by E2+TNFα are clinically relevant since 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 crosstalk between ER and NFκB 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.