title: Estrogen receptor subtype- and promoter-specific modulation of aryl hydrocarbon receptor-dependent transcription.
abstract: In this study, we examined the role of estrogen receptors (ER) in aryl hydrocarbon receptor (AHR)-dependent transactivation. Chromatin immunoprecipitation assays showed that AHR agonists differentially induced recruitment of ERalpha to the AHR target genes CYP1A1 and CYP1B1. Cotreatment with 17beta-estradiol significantly increased beta-naphthoflavone (BNF)- and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced recruitment of ERalpha to CYP1A1, whereas 3,3'-diindolylmethane induced promoter occupancy of ERalpha at CYP1A1 that was unaffected by cotreatment with 17beta-estradiol. Cyclical recruitment of AHR and ERalpha to CYP1A1 was only observed in cells treated with BNF. Stable and subtype-specific knockdown of ERalpha or ERbeta using shRNA showed that suppression of ERalpha significantly reduced, whereas knockdown of ERbeta significantly enhanced, AHR agonist-induced Cyp1a1 expression in HC11 mouse mammary epithelial cells. AHR agonist-induced Cyp1b1 expression was reduced by ERbeta knockdown but unaffected by ERalpha knockdown. The siRNA-mediated knockdown of ERalpha in MCF-7 human breast cancer cells did not affect 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent regulation of CYP1A1 and CYP1B1 mRNA expression. In agreement with our in vitro findings in the HC11 cells, ERalpha knockout mice exhibit reduced BNF-dependent induction of Cyp1a1 mRNA. These results establish ligand- and promoter-specific influences on the cyclical recruitment patterns for AHR and show ER species-, subtype-, and promoter-specific modulation of AHR-dependent transcription.
authors.affiliation: Department of Biosciences and Nutrition at Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Wihlén
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Ahmed
authors.forename: José
authors.initials: J
authors.lastname: Inzunza
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection
chemical_list: C497396:ARNT protein, human; C497397:Arnt protein, mouse; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1