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J Biol Chem. 2010 Oct 8;285(41):31100-6. doi: 10.1074/jbc.M110.155309. Epub 2010 Aug 12.

Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements.

Author information

1
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

Abstract

Constitutive activation of NFκB in estrogen receptor (ER)-positive breast cancer is associated with tumor recurrence and development of anti-estrogen resistance. Furthermore, a gene expression signature containing common targets for ER and NFκB has been identified and found to be associated with the more aggressive luminal B intrinsic subtype of ER-positive breast tumors. Here, we describe a novel mechanism by which ER and NFκB cooperate to up-regulate expression of one important gene from this signature, ABCG2, which encodes a transporter protein associated with the development of drug-resistant breast cancer. We and others have confirmed that this gene is regulated primarily by estrogen in an ER- and estrogen response element (ERE)-dependent manner. We found that whereas proinflammatory cytokines have little effect on this gene in the absence of 17β-estradiol, they can potentiate ER activity in an NFκB-dependent manner. ER allows the NFκB family member p65 to access a latent NFκB response element located near the ERE in the gene promoter. NFκB recruitment to the gene is, in turn, required to stabilize ER occupancy at the functional ERE. The result of this cooperative binding of ER and p65 at adjacent response elements leads to a major increase in both ABCG2 mRNA and protein expression. These findings indicate that estrogen and inflammatory factors can modify each other's activity through modulation of transcription factor accessibility and/or occupancy at adjacent response elements. This novel transcriptional mechanism could have important implications in breast cancer, where both inflammation and estrogen can promote cancer progression.

PMID:
20705611
PMCID:
PMC2951183
DOI:
10.1074/jbc.M110.155309
[Indexed for MEDLINE]
Free PMC Article

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