IRS-1 expression and activation are not sufficient to activate downstream pathways and enable IGF-I growth response in estrogen receptor negative breast cancer cells

IGF-responsive breast cancer cells activate insulin receptor substrate (IRS)-1 after IGF-1 treatment. To determine if IRS-I expression was sufficient to enable IGF-responsiveness, two IGF-1 unresponsive breast cancer cell lines (MDA-MB-435A and MDA-MB-468) were transfected with IRS-1. While IGF-I caused tyrosine phosphorylation of IRS-I in both transfected cell lines, increased MAP kinase activity was not seen. IGF-1 treatment of 435A IRS-1 transfected cells resulted in minimal increased P13 kinase activity associated with IRS-l,while IRS-2/P13 kinase was greatly reduced. in MDA-MB-468 IRS-I transfected cells, IGF-I caused increased IRS-1 associated P13 kinase activity compared to parental cells, but at levels far below those observed in IGF-responsive MCF-7 cells. The transfected cells were also not responsive to IGF-1 in monolayer growth. Thus, IRS-1 expression and activation alone are insufficient to mediate a proliferative response to IGF-1 in breast cancer cells, and it is likely that maximal activation of downstream signaling pathways must also occur. (C) 1999 Harcourt Publishers Ltd.