title: A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein.
abstract: There is concern that ingestion of dietary phytoestrogens may increase risk of estrogen receptor alpha (ERα)-positive breast cancer. The prenylflavone icaritin, a phytoestrogen consumed in East Asian societies for its perceived beneficial effects on bone health, stimulated the growth of breast cancer (MCF-7) cells at low concentrations. Although acting like an estrogenic ligand, icaritin exerted an unexpected suppressive effect on estrogen-stimulated breast cancer cell proliferation and gene expression at higher concentrations. Like estradiol, icaritin could dose-dependently destabilize ERα protein. However, destabilization of ERα by the estradiol/icaritin combination was profound and greater than that observed for either compound alone. Microarray gene expression analyses implicated aryl hydrocarbon receptor (AhR) signaling for this suppressive effect of icaritin. Indeed, icaritin was an AhR agonist that competitively reduced specific binding of a potent AhR agonist and increased expression of the AhR-regulated gene CYP1A1. When AhR was knocked down by small interfering RNA, the suppressive effect of icaritin on estradiol-stimulated breast cancer cell growth and gene expression was abolished, and ERα protein stability was partially restored. Similarly in an athymic nude mouse model, icaritin restricted estradiol-stimulated breast cancer xenograft growth and strongly reduced ERα protein levels. Overall, our data support the feasibility for the development of dual agonists like icaritin, which are estrogenic but yet, through activating AhR-signaling, can destabilize ERα protein to restrict ERα-positive breast cancer cell growth.
authors.affiliation: Department of Obstetrics and Gynecology, National University Hospital, Yong Loo Lin School of Medicine, Lower Kent Ridge Road, 119074 Singapore.
authors.forename: Chi Tze
authors.initials: CT
authors.lastname: Tiong
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Shi Jun
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Anatoly
authors.initials: A
authors.lastname: Soshilov
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.forename: Lawrence Soon-U
authors.initials: LS
authors.lastname: Lee
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
authors.forename: Shih Peng
authors.initials: SP
authors.lastname: Wong
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Eu-Leong
authors.initials: EL
authors.lastname: Yong
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D005419:Flavonoids; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D004958:Estradiol; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D046988:Proteasome Endopeptidase Complex; C499403:icaritin