title: Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens.
abstract: Because little is known about the actions of botanical estrogens (BEs), widely consumed by menopausal women, we investigated the mechanistic and cellular activities of some major BEs. We examined the interactions of genistein, daidzein, equol, and liquiritigenin with estrogen receptors ERα and ERβ, with key coregulators (SRC3 and RIP140) and chromatin binding sites, and the regulation of gene expression and proliferation in MCF-7 breast cancer cells containing ERα and/or ERβ. Unlike the endogenous estrogen, estradiol (E2), BEs preferentially bind to ERβ, but their ERβ-potency selectivity in gene stimulation (340- to 830-fold vs. E2) is enhanced at several levels (coregulator recruitment, chromatin binding); nevertheless, at high (0.1 or 1 μM) concentrations, BEs also fully activate ERα. Because ERα drives breast cancer cell proliferation and ERβ dampens this, the relative levels of these two ERs in target cells and the BE dose greatly affect gene expression and proliferative response and will be crucial determinants of the potential benefits vs. risks of BEs. Our findings reveal key and novel mechanistic differences in the estrogenic activities of BEs vs. E2, with BEs displaying patterns of activity distinctly different from those seen with E2 and provide valuable information to inform future studies.
authors.affiliation: 1Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine at Urbana-Champaign, Urbana, IL 61801, USA. katzenel@illinois.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
authors.forename: Teresa
authors.initials: T
authors.lastname: Martin
authors.forename: Muthu
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: Kathryn
authors.initials: K
authors.lastname: Carlson
authors.forename: Ikhlas
authors.initials: I
authors.lastname: Khan
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Smillie
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.forename: Sateesh C K
authors.initials: SC
authors.lastname: Rotte
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001665:Binding Sites; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D048789:Phytoestrogens / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D048789:Phytoestrogens; D004958:Estradiol; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3
keywords: breast cancer cells; chromatin binding; gene regulation; proliferation