p66(Shc) isoform down-regulated and not required for HER-2/neu signaling pathway in human breast cancer cell lines with HER-2/neu overexpression

The HER2/neu protooncogene encodes a transmembrane receptor tyrosine kinase of M(r) 185 kDa (called p185) which is structurally and functionally homologous to the epidermal growth factor receptor. She proteins are important downstream signal transducers of receptor tyrosine kinases. We reported here a novel finding that p66(Shc) was absent or nearly absent in p185-overexpressing breast cancer cells. This inverse correlation of p185 overexpression and p66(Shc) expression is probably specific to breast cancer cells because this phenomenon was not observed in p185-overexpressing human ovarian, lung, or oral cancer cells, or mouse fibroblast cells. In contrast, the p52(Shc) and p46(Shc) isoforms were expressed at similar levels in both p185-overexpressing and p185 basal level breast cancer cell lines. Furthermore, tyrosine phosphorylation of p52(Shc) and p46(Shc) and subsequent formation of Shc/Grb2 complex were detected in breast cancer cells in which the p185 tyrosine kinase is activated, indicating that p66(Shc) is not required for mediating the HER-2/neu signaling pathway in breast cancer cells. (C) 1996 Academic Press, Inc.