SHC-alpha 5 beta 1 integrin interactions regulate breast cancer cell adhesion and motility

The oncogenic SHC proteins are signaling substrates for most receptor and c ytoplasmic tyrosine kinases (TKs) and have been implicated in cellular grow th, transformation, and differentiation. In tumor cells overexpressing TKs, the levels of tyrosine phosphorylated SHC are chronically elevated. The si gnificance of amplified SHC signaling in breast tumorigenesis and metastasi s remains unknown. Here we demonstrate that seven- to ninefold overexpressi on of SHC significantly altered interactions of cells with fibronectin (FN) . Specifically, in human breast cancer cells overexpressing SHC (MCF-7/SHC) the association of SHC with alpha 5 beta 1 integrin (FN receptor) was incr eased, spreading on FN was accelerated, and basal growth on FN was reduced. These effects coincided with an early decline of adhesion-dependent MAP ki nase activity. Basal motility of MCF-7/SHC cells on FN was inhibited relati ve to that in several cell lines with normal SHC levels. However, when EGF or IGF-I was used as the chemoattractant, the locomotion of MCF-7/SHC cells was greatly (approx fivefold) stimulated, while it was only minimally alte red in the control cells. These data suggest that SHC is a mediator of the dynamic regulation of cell adhesion and motility on FN in breast cancer cel ls, (C) 1999 Academic Press.