title: Activation of mitogen- and stress-activated kinase 1 is required for proliferation of breast cancer cells in response to estrogens or progestins.
abstract: Growth of breast cancers is often dependent on ovarian steroid hormones making the tumors responsive to antagonists of hormone receptors. However, eventually the tumors become hormone independent, raising the need to identify downstream targets for the inhibition of tumor growth. One possibility is to focus on the signaling mechanisms used by ovarian steroid hormones to induce breast cancer cell proliferation. Here we report that the mitogen- and stress-activated kinase 1 (MSK1) could be a potential druggable target. Using the breast cancer cell line T47D, we show that estrogens (E2) and progestins activate MSK1, which forms a complex with the corresponding hormone receptor. Inhibition of MSK1 activity with H89 or its depletion by MSK1 short hairpin RNAs (shRNAs) specifically abrogates cell proliferation in response to E2 or progestins without affecting serum-induced cell proliferation. MSK1 activity is required for the transition from the G1- to the S-phase of the cell cycle and inhibition of MSK1 compromises both estradiol- and progestin-dependent induction of cell cycle genes. ChIP-seq experiments identified binding of MSK1 to progesterone receptor-binding sites associated with hormone-responsive genes. MSK1 recruitment to epigenetically defined enhancer regions supports the need of MSK1 as a chromatin remodeler in hormone-dependent regulation of gene transcription. In agreement with this interpretation, expression of a histone H3 mutated at S10 eliminates the hormonal effect on cell proliferation and on induction of relevant target genes. Finally, we show that E2- or progestin-dependent growth of T47D cells xenografted in immunodefficient mice is inhibited by depletion of MSK1, indicating that our findings are not restricted to cultured cells, and that MSK1 plays an important role for hormone-dependent breast cancer growth in a more physiological context.
authors.affiliation: 1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Reyes
authors.affiliation: 1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ballaré
authors.affiliation: 1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Castellano
authors.affiliation: 1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Soronellas
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, CIBER-BBN, Barcelona, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Bagó
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, CIBER-BBN, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Blanco
authors.affiliation: 1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Beato
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D011372:Progestins / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011980:Receptors, Progesterone / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002843:Chromatin; D004967:Estrogens; D006657:Histones; D011372:Progestins; D047428:Protein Kinase Inhibitors; D011980:Receptors, Progesterone; D004958:Estradiol; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1