title: DHEA metabolites activate estrogen receptors alpha and beta.
abstract: Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ)-regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, androstenedione, DHEA, androstenediol, and 7-oxo DHEA stimulated reporter activity. ER antagonists ICI 182,780 (fulvestrant) and 4-hydroxytamoxifen, general P450 inhibitor miconazole, and aromatase inhibitor exemestane inhibited activation by DHEA or metabolites in transfected cells. ERβ-selective antagonist R,R-THC (R,R-cis-diethyl tetrahydrochrysene) inhibited DHEA and DHEA metabolite transcriptional activity in ERβ-transfected cells. Expression of endogenous estrogen-regulated genes: pS2, progesterone receptor, cathepsin D1, and nuclear respiratory factor-1 was increased by DHEA and its metabolites in an ER-subtype, gene, and cell-specific manner. DHEA metabolites, but not DHEA, competed with 17β-estradiol for ERα and ERβ binding and stimulated MCF-7 cell proliferation, demonstrating that DHEA metabolites interact directly with ERα and ERβin vitro, modulating estrogen target genes in vivo.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Kristy K Michael
authors.initials: KK
authors.lastname: Miller
authors.forename: Numan
authors.initials: N
authors.lastname: Al-Rayyan
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Ivanova
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Mattingly
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ripp
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
authors.forename: Russell A
authors.initials: RA
authors.lastname: Prough
mesh_terms: D015114:Androstenediol / Q000494:pharmacology; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006224:Cricetinae; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008825:Miconazole / Q000494:pharmacology; D020218:Response Elements; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D004958:Estradiol; D008825:Miconazole; D015114:Androstenediol; D049410:Luciferases, Renilla; D001616:beta-Galactosidase