DIFFERENTIAL ROLES OF IRS-1 AND SHC SIGNALING PATHWAYS IN BREAST-CANCER CELLS

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 ma intenance of the neoplastic phenotype is largely unknown. The activati on 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 postreceptor signaling molecules, ins ulin receptor substrate-I (IRS-I) (a major substrate of the IGF-IR) an d SHC (a common substrate of tyrosine kinase receptors), we developed several MCF-7-derived cell clones in which the synthesis of either IRS -I or SHC was blocked by antisense RNA. In MCF-7 cells, down-regulatio n of IRS-I by 80-85% strongly suppressed anchorage-dependent and -inde pendent growth and induced apoptotic cell death under growth factor-an d estrogen-reduced conditions. The reduction of SHC levels by approxim ately 50% resulted in the inhibition of monolayer and anchorage-indepe ndent growth but did not decrease cell survival. Importantly, cell agg regation and the ability of cells to survive on the extracellular matr ix were inhibited in MCF-7/anti-SHC clones, but not in MCF-7/anti-IRS- I clones. Cell motility toward IGF was not attenuated in any of the te sted cell lines, but motility toward EGF was decreased in MCF-7/anti-S HC clones, Our results suggest that in MCF-7 cells: 1) both IRS-I and SHC are implicated in the control of monolayer and anchorage-independe nt growth; 2) IRS-I is critical to support cell survival; 3) SHC is in volved in EGF-dependent motility; and 4) normal levels of SHC, but not IRS-I, are necessary for the formation and maintenance of cell-cell i nteractions. (C) 1997 Wiley-Liss, Inc.