Proposed model for potentiation of E2-regulated ABCG2 expression during inflammation.
Estrogen receptor (ER) and NFκB are key transcription factors that regulate breast cancer cell proliferation and survival. While most studies have focused on how these factors influence each others’ transcriptional activity, this article describes a novel mechanism by which ER and NFκB work together to regulate expression of the multidrug transporter ABCG2, which is known to be involved in breast cancer drug resistance. The authors found that under proinflammatory conditions, these two transcription factors are cooperatively recruited to the promoter region of the ABCG2 gene at adjacent sites. ER allows the NFκB family member p65 to access a latent NFκB response element located near the estrogen response element (ERE) in the gene promoter; in turn, this p65 recruitment is required to stabilize ER occupancy at the functional ERE. Once present together on the ABCG2 promoter, ER and p65 act synergistically to potentiate mRNA and subsequent protein expression. This study has important implications for patients with ER-positive breast tumors, as it reveals a mechanism whereby inflammation enhances the expression of an ER target gene, which, in turn, can exacerbate breast tumor progression by promoting drug resistance.
Proinflammatory Cytokines Enhance Estrogen-dependent Expression of the Multidrug Transporter Gene ABCG2 through Estrogen Receptor and NFκB Cooperativity at Adjacent Response Elements
Madhumita Pradhan, Leslie A. Bembinster, Sarah C. Baumgarten and Jonna Frasor
J. Biol. Chem., published online Aug. 12, 2010
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