title: Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2.
abstract: Progesterone action contributes to the signaling of many growth factor pathways relevant to breast cancer tumor biology, including the insulin-like growth factor (IGF) system. Previous work has shown that insulin receptor substrate-2 (IRS-2) but not IRS-1 levels were regulated by progestin in progesterone receptor-B (PR-B) isoform expressing MCF-7 cells (C4-12 PR-B). Furthermore, type 1 IGF receptor (IGF1R) signaling via IRS-2 correlated with the increased cell migration observed in a number of breast cancer cell lines. Consequently, in this study, we examined whether the elevation of IRS-2 protein induced by progestin was sufficient to promote IGF-I-stimulated cell motility. Treatment of C4-12 PR-B cells with progestin shifted the balance of phosphorylation from IRS-1 to IRS-2 in response to IGF-I. This shift in IRS-2 activation was associated with enhanced migration in C4-12 PR-B cells pretreated with progestin, but had no effect on cell proliferation or survival. Treatment of C4-12 PR-B cells with RU486, an antiprogestin, inhibited IGF-induced cell migration. Attenuation of IRS-2 expression using small interfering RNA resulted in decreased IGF-stimulated motility. In addition, IRS-2 knockdown resulted in an abrogation of PKB/Akt phosphorylation but not mitogen-activated protein kinase. Consequently, LY294002, a phosphoinositide-3-kinase inhibitor, abolished IGF-induced cell motility in progestin-treated C4-12 PR-B cells. These data show a role for the PR in functionally promoting growth factor signaling, showing that levels of IRS proteins can determine IGF-mediated biology, PR-B signaling regulates IRS-2 expression, and that IRS-2 can mediate IGF-induced cell migration via phosphoinositide-3-kinase in breast cancer cells.
authors.affiliation: Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.forename: Sara A
authors.initials: SA
authors.lastname: Byron
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011372:Progestins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011372:Progestins; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases