title: Differential roles of IRS-1 and SHC signaling pathways in breast cancer cells.
abstract: Several polypeptide growth factors stimulate breast cancer growth and may be involved in tumor progression. However, the relative importance of diverse growth factor signaling pathways in the development and maintenance of the neoplastic phenotype is largely unknown. The activation of such growth factor receptors as the insulin-like growth factor I receptor (IGF-I R), erbB-type receptors (erbB Rs) and FGF receptors (FGF Rs) controls the phenotype of a model breast cancer cell line MCF-7. To evaluate the function of 2 post-receptor signaling molecules, insulin receptor substrate-1 (IRS-1) (a major substrate of the IGF-IR) and SHC (a common substrate of tyrosine kinase receptors), we developed several MCF-7-derived cell clones in which the synthesis of either IRS-1 or SHC was blocked by antisense RNA. In MCF-7 cells, down-regulation of IRS-1 by 80-85% strongly suppressed anchorage-dependent and -independent growth and induced apoptotic cell death under growth factor- and estrogen-reduced conditions. The reduction of SHC levels by approximately 50% resulted in the inhibition of monolayer and anchorage-independent growth but did not decrease cell survival. Importantly, cell aggregation and the ability of cells to survive on the extracellular matrix were inhibited in MCF-7/anti-SHC clones, but not in MCF-7/anti-IRS-1 clones. Cell motility toward IGF was not attenuated in any of the tested cell lines, but motility toward EGF was decreased in MCF-7/anti-SHC clones. Our results suggest that in MCF-7 cells: 1) both IRS-1 and SHC are implicated in the control of monolayer and anchorage-independent growth; 2) IRS-1 is critical to support cell survival; 3) SHC is involved in EGF-dependent motility; and 4) normal levels of SHC, but not IRS-1, are necessary for the formation and maintenance of cell-cell interactions.
authors.affiliation: Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Nolan
authors.forename: L
authors.initials: L
authors.lastname: Jankowska
authors.forename: M
authors.initials: M
authors.lastname: Prisco
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: M A
authors.initials: MA
authors.lastname: Guvakova
authors.forename: E
authors.initials: E
authors.lastname: Surmacz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D016372:RNA, Antisense / Q000494:pharmacology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D013002:Somatomedins / Q000494:pharmacology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011506:Proteins; D016372:RNA, Antisense; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D013002:Somatomedins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004815:Epidermal Growth Factor