title: Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation.
abstract: The 40S ribosomal S6 kinase 1 (S6K1) is an important regulator of cell growth. Expression of S6K1 is often elevated in breast cancer cells. However, the transcriptional mechanism of S6K1 overexpression is not understood. In this report, we demonstrate that estrogen activates expression of S6K1 via estrogen receptor (ER)α in ER-positive breast cancer cells. We also show that estrogen acts on the proximal promoter of the S6K1 gene in a mechanism involving the transcriptional factor GATA-3. Finally, we provide data that support the importance of estrogenic regulation of S6K1 expression in breast cancer cell proliferation. S6K1 directly phosphorylates and regulates ligand-independent activity of ERα, while ERα upregulates S6K1 expression. This S6K1-ERα relationship creates a positive feed-forward loop in control of breast cancer cell proliferation. Furthermore, the co-dependent association between S6K1 and ERα may be exploited in the development of targeted breast cancer therapies.
authors.affiliation: Department of Biology, Stern College for Women of Yeshiva University, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Maruani
authors.forename: T N
authors.initials: TN
authors.lastname: Spiegel
authors.forename: E N
authors.initials: EN
authors.lastname: Harris
authors.forename: A S
authors.initials: AS
authors.lastname: Shachter
authors.forename: H A
authors.initials: HA
authors.lastname: Unger
authors.forename: S
authors.initials: S
authors.lastname: Herrero-González
authors.forename: M K
authors.initials: MK
authors.lastname: Holz
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D050990:GATA3 Transcription Factor; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1