Mechanism by which p66 Shc Suppresses Breast Cancer Tumorgenicity

摘要

Considerable evidence suggests that poor prognosis in breast cancer may be due to overly-activated growth-factor receptors such as ErbB2, TGF-1, EGFR, and c-Met. A downstream signaling protein common to all these kinases is the adapter protein, Shc. Shc helps activated growth-factor receptors transfer signals to the c-Ras-MAP kinase pathway. Additionally, Shc appears to signal to Jun kinase, PI3kinase and to c-Myc (implicated in cell proliferation, apoptosis and the stress response). Recently we have reported that many human breast cancer cell lines (but not non-cancerous breast epithelial cell lines) not only harbor constitutively activated (phosphorylated on tyronsine 317) Shc proteins, but also breast cancer cells appear to require signaling from Shc in order to proliferate. A third, 66-kDa splicing isoform, of Shc (p66-Shc) can act as a feedback inhibitor of growth-factor signaling to MAP kinase and to c-fos, and acts as an apoptotic sensitizer for oxidative stress in some cell lines. We have recently reported a strong negative correlation between the cellular levels of activated Shc and cellular expression of the inhibitor p66-Shc isoform. We have also demonstrated that p66-Sch acts as a strong negative growth regulator, as measured by their inability to form colonies in soft agar.