Is the 66-kDa Isoform of the Shc Adapter Protein a Tumor Suppressor for Growth-Factor-Receptor-Dependent Breast Cancers?

Abstract : In contrast to its 46- and 52-kDa isoforms, the 66-kDa Shc protein functions as a feedback inhibitor of growth-factor signaling and as an apoptotic sensitizer to oxidative stress. Interestingly, p66 Shc is absent or expressed at reduced levels m most breast cancer cell lines. We have begun to explore the regulation of the p66 Shc isoform expression and to determine the role of its reduced expression in the neoplastic phenotype. Pulse-chase 35S-Met metabolic labeling and semi-quantitative PCR studies suggest that the reduced expression of p66 Shc is due to regulation at the level of mRNA stability or gene transcription. Forced re-expression of p66-Shc inhibited the ability of breast cancer cell lines to form colonies on soft agar, an in vitro correlate of tumorgenicity. Re-expressed p66 Shc appears to be phosphorylated on tyrosine(Y317) and on serine(S36) residues, to be complexed with Grb2 (29-kDa), and proteins of 22-, 28-, 45-, 50-, 85-, and 105-kDa proteins. The re-expressed p66 Shc does not appear to lower activity of either Erk-1, Erk-2 or phosphatidyl-inositol 3-kinase. The ability of re-expressed p66 Shc to inhibit anchorage-independent growth indicates that the 66-kDa Shc isoform may act as a tumor suppressor for many breast cancers.