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Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.

ABSTRACT: Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor-alpha (ERalpha) to AHR-regulated genes and that AHR is recruited to ERalpha-regulated genes. However, these findings were limited to a small number of well-characterized AHR- or ERalpha-responsive genes with little knowledge of what was occurring at other genomic regions. In this study, we showed using chromatin immunoprecipitation followed by hybridization to promoter focused microarrays (ChIP-chip) that 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment significantly increased the overlap of genomic regions bound by both AHR and ERalpha. Conventional and sequential ChIPs confirmed the recruitment of AHR and ERalpha to many of the identified regions. Transcription factor binding site analysis revealed an overrepresentation of aryl hydrocarbon receptor response elements in regions bound by both AHR and ERalpha, suggesting that AHR was the important factor determining the recruitment of ERalpha to these regions. RNA interference-mediated knockdown of AHR confirmed its requirement for the recruitment of ERalpha to some, but not all, of the shared regions. Our findings demonstrate not only that dioxin induces the recruitment of ERalpha to AHR target genes but also that AHR is recruited to estrogen-responsive regions in a gene-specific manner, suggesting that AHR utilizes both of these mechanisms to modulate estrogen-dependent signaling.

SUBMITTER: Ahmed S

PROVIDER: S-EPMC2999625 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.

Ahmed Shaimaa S Valen Eivind E Sandelin Albin A Matthews Jason J

Toxicological sciences : an official journal of the Society of Toxicology 20090702 2

Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor-alpha (ERalpha) to AHR-regulated genes and that AHR is recruited to ERalpha-regulated genes. However, these findings were limited to a small number of well-characterized AHR- or ERalpha-responsive genes with little knowledge of what was occurring at other genomic regions. In this study, we showed using chromatin immunoprecipitation followed by hybridization to promoter focused mi ...[more]

PMID: 19574409

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Project description:Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women's health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 ?g/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in "normal" vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast cancer patients should avoid red clover and isoflavone based BDSs when making choices for menopausal symptom relief.

Dataset Information

Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.

Publications

Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.

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