Progesterone Receptor-B Regulation of Insulin-Like Growth Factor–Stimulated Cell Migration in Breast Cancer Cells via Insulin Receptor Substrate-2
Copyright policy )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. (Mol Cancer Res 2008;6(9):1491–8)
- Baylor College of Medicine United States
- Masonic Cancer Center United States
- University of Minnesota Morris United States
Intracellular Signaling Peptides and Proteins, Apoptosis, Breast Neoplasms, Phosphoproteins, Gene Expression Regulation, Neoplastic, Phosphatidylinositol 3-Kinases, Cell Movement, Cell Adhesion, Insulin Receptor Substrate Proteins, Humans, Immunoprecipitation, Female, Insulin-Like Growth Factor I, Mitogen-Activated Protein Kinases, Phosphorylation, Progestins, Receptors, Progesterone, Proto-Oncogene Proteins c-akt, Adaptor Proteins, Signal Transducing, Cell Proliferation
Intracellular Signaling Peptides and Proteins, Apoptosis, Breast Neoplasms, Phosphoproteins, Gene Expression Regulation, Neoplastic, Phosphatidylinositol 3-Kinases, Cell Movement, Cell Adhesion, Insulin Receptor Substrate Proteins, Humans, Immunoprecipitation, Female, Insulin-Like Growth Factor I, Mitogen-Activated Protein Kinases, Phosphorylation, Progestins, Receptors, Progesterone, Proto-Oncogene Proteins c-akt, Adaptor Proteins, Signal Transducing, Cell Proliferation
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