title: Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor beta and AP-1 recruitment to adjacent promoter binding sites.
abstract: Little is known about endogenous estrogen receptor β (ERβ) gene targets in human breast cancer. We reported that estradiol (E(2)) induces nuclear respiratory factor-1 (NRF-1) transcription through ERα in MCF-7 breast cancer cells. Here we report that 4-hydroxytamoxifen (4-OHT), with an EC(50) of ~1.7 nM, increases NRF-1 expression by recruiting ERβ, cJun, cFos, CBP, and RNA polymerase II to and dismissing NCoR from the NRF1 promoter. Promoter deletion and transient transfection studies showed that the estrogen response element (ERE) is essential and that an adjacent AP-1 site contributes to maximal 4-OHT-induced NRF-1 transcription. siRNA knockdown of ERβ revealed that ERβ inhibits basal NRF-1 expression and is required for 4-OHT-induced NRF-1 transcription. An AP-1 inhibitor blocked 4-OHT-induced NRF-1 expression. The 4-OHT-induced increase in NRF-1 resulted in increased transcription of NRF-1 target CAPNS1 but not CYC1, CYC2, or TFAM despite increased NRF-1 coactivator PGC-1α protein. The absence of TFAM induction corresponds to a lack of Akt-dependent phosphorylation of NRF-1 with 4-OHT treatment. Overexpression of NRF-1 inhibited 4-OHT-induced apoptosis and siRNA knockdown of NRF-1 increased apoptosis, indicating an antiapoptotic role for NRF-1. Overall, NRF-1 expression and activity is regulated by 4-OHT via endogenous ERβ in MCF-7 cells.
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: Margarita M
authors.initials: MM
authors.lastname: Ivanova
authors.forename: Kristen H
authors.initials: KH
authors.lastname: Luken
authors.forename: Amber S
authors.initials: AS
authors.lastname: Zimmer
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Lenzo
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Smith
authors.forename: Maia W
authors.initials: MW
authors.lastname: Arteel
authors.forename: Tara J
authors.initials: TJ
authors.lastname: Kollenberg
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Mattingly
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000502:physiology; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051266:Nuclear Respiratory Factor 1; D012176:Retinoids; C106195:SR 11302; D018808:Transcription Factor AP-1; D013629:Tamoxifen; C016601:afimoxifene