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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen.

Authors: Hockings, Jennifer K; Thorne, Patricia A; Kemp, Michael Q; Morgan, Sherif S; Selmin, Ornella; Romagnolo, Donato F

Published In Cancer Res, (2006 Feb 15)

Abstract: In sporadic breast cancers, BRCA-1 expression is down-regulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-alpha (ER alpha) complex to the proximal BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3'-methoxy-4'-nitroflavone; (b) transient expression in ER alpha-negative HeLa cells of ER alpha lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5'-GCGTG-3') located upstream of the ER alpha-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ER alpha plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen.

PubMed ID: 16489025 Exiting the NIEHS site

MeSH Terms: BRCA1 Protein/biosynthesis; BRCA1 Protein/genetics; Benzo(a)pyrene/metabolism; Benzo(a)pyrene/pharmacology; Breast Neoplasms/genetics; Estradiol/pharmacology*; Estrogen Receptor alpha/metabolism*; Gene Expression Regulation, Neoplastic/drug effects; Gene Expression Regulation, Neoplastic/physiology; Genes, BRCA1/drug effects; Genes, BRCA1/physiology*; HeLa Cells; Humans; Ligands; Polychlorinated Dibenzodioxins/metabolism; Polychlorinated Dibenzodioxins/pharmacology; Promoter Regions, Genetic/drug effects; RNA, Messenger/biosynthesis; RNA, Messenger/genetics; Receptor Cross-Talk/drug effects; Receptor Cross-Talk/physiology; Receptors, Aryl Hydrocarbon/antagonists & inhibitors; Receptors, Aryl Hydrocarbon/metabolism*; Transcription Factor AP-1/metabolism; Transcriptional Activation/drug effects; Transcriptional Activation/physiology; Transfection

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