| The estrogen receptor (ER) and NFκB are crucial transcription factors involved in cell proliferation and survival. The well-studied modality of ER-NFκB crosstalk is transrepression whereby ER represses NFκB activity and vice versa. However, a recent gene profiling study from our lab, in breast cancer cells treated with estradiol (E2), TNFα, a pro-inflammatory cytokine which is a potent activator of NFκB, or both, additionally identified an 80-gene signature enhanced by E2+TNFα that was enriched in the Luminal B subtype of more aggressive ER-positive breast tumors. The mechanism underlying this positive crosstalk was examined for two genes that play important roles in cancer cell drug response and survivalABCG2 and BIRC3. Both genes are greatly up-regulated by E2+TNFα, compared to E2 or TNFα alone, in an ER and NFκB-dependent manner.;ABCG2 and BIRC3 promoters have a similar arrangement of an ERE and two NFκBREs but the functionality and/or accessibility of the response elements differ for the two genes. For ABCG2, the ERE is functional as it recruits ER and drives gene expression by E2 alone. The NFκBRE, however, may recruit the NFκB subunit, p50, but appears to be functionally inactive as TNFα alone cannot regulate the gene. However, in the presence of E2+TNFα, ER allows recruitment of the transcriptionally active NFκB member, p65, to the NFκBRE, rendering it functional and able to enhance E2 action at ABCG2. Once recruited, NFκB is required to enhance ER occupancy at the gene. For BIRC3, the NFκBREs are functional as they recruit NFκB and regulate gene expression with TNFα alone. Here, the ERE appears non-functional as E2 one cannot regulate the gene. However, the ERE becomes functionally active with E2+TNFα, following ER recruitment in an NFκB-dependent manner and is required to potentiate TNFα action at BIRC3. Presence of both ER and NFκB at ABCG2 and BIRC3 promoters, in response to E2+TNFα, ultimately leads to enhanced regulation of the two genes.;Thus, ER and NFκB can modulate each other's activity at ABCG2 and BIRC3. These findings suggest that estrogen and pro-inflammatory cytokines may act together to increase gene expression by conferring functionality upon inherently non-functional EREs or NFκBRES in a gene-specific manner. This phenomenon may play an important role in pathologies of hormone-dependent tissues with an accompanying inflammatory component, including breast cancer. |
