title: Synergistic proliferative action of insulin-like growth factor I and 17 beta-estradiol in MCF-7S breast tumor cells.
abstract: We have analyzed the mechanism by which the combination of insulin-like growth factor I (IGF-I) and 17 beta-estradiol (E2) induces cell cycle progression in MCF-7S cells. This cell line differs from many other breast cancer-derived cell lines in that E2 (1 nM) does not induce cell cycle progression, whereas the combination of submitogenic concentrations of IGF-I (2 ng/ml) and E2 does. We find that addition of IGF-I to MCF-7S cells leads to a dose-dependent activation of the IGF type I receptor and of the MAP kinase and PI3-kinase signaling pathways. No synergy of IGF-I and E2 was detected in the activation of these signaling cascades. In terms of cell cycle-related molecules, we find that IGF-I dose-dependently raises cyclin D1 levels in serum-starved cells. Subsequent activation of cyclin E/CDK2, hyperphosphorylation of pRb, and DNA synthesis are only induced by mitogenic concentrations of IGF-I (> or =20 ng/ml). Treatment of the cells with E2 also results in the induction of cyclin D1, but in the absence of IGF-I the cells remain arrested in G1 phase. We conclude that in MCF-7S cells, the synergistic action of E2 and IGF-I derives from the ability of both hormones to induce cyclin D1 expression. The action of IGF-I is required in these cells to induce activity of the cyclin D1/CDK4 complex, which triggers progression through the cell cycle.
authors.affiliation: Utrecht Graduate School of Developmental Biology, University Medical Center Utrecht, Utrecht, 3508 AB, The Netherlands. I.H.L.Hamelers@med.uu.nl
authors.forename: Irene H L
authors.initials: IH
authors.lastname: Hamelers
authors.forename: Richard F M A
authors.initials: RF
authors.lastname: van Schaik
authors.forename: Hetty A A M
authors.initials: HA
authors.lastname: van Teeffelen
authors.forename: John S
authors.initials: JS
authors.lastname: Sussenbach
authors.forename: Paul H
authors.initials: PH
authors.lastname: Steenbergh
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D042846:CDC2-CDC28 Kinases; D019938:Cyclin D1; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004958:Estradiol; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011960:Receptors, Estrogen; D013936:Thymidine; C495894:CDK2 protein, human