Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements
| Autor: | Sarah C. Baumgarten, Leslie A. Bembinster, Madhumita Pradhan, Jonna Frasor |
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| Rok vydání: | 2010 |
| Předmět: |
Response element
Estrogen receptor Breast Neoplasms Biology Response Elements Biochemistry Proinflammatory cytokine Cell Line Tumor Transcriptional regulation ATP Binding Cassette Transporter Subfamily G Member 2 Humans Gene Regulation RNA Messenger Molecular Biology Transcription factor Estrogen receptor beta Hormone response element Regulation of gene expression Estradiol Transcription Factor RelA Estrogens Cell Biology Neoplasm Proteins Up-Regulation Gene Expression Regulation Neoplastic Receptors Estrogen Drug Resistance Neoplasm Cancer research Cytokines ATP-Binding Cassette Transporters Female hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of biological chemistry. 285(41) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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