Mechanism by Which p66 Shc Suppresses Breast Cancer Timorgenicity

摘要

Considerable evidence suggests that poor prognosis in breast cancer is due to the over expression of cell surface receptor tyrosine kinases. A molecule downstream in the signaling pathways common to all these receptors is the small adaptor protein Shc. The Shc adapter protein transmits signals from the activated growth factor receptor to Ras. There are three Shc isoforms of 46, 52, and 66 kDa. The 52- and 46-kDa isoforms, which differ in their 5' initiation site, are ubiquitously expressed. Our laboratory has previously reported that most cell lines derived from breast cancers harbor constitutively tyrosine phosphorylated p46- and p52-Shc. The p66-Shc isoform, expressed through the use of an alternative promoter, contains an additional 110 amino- acid CH2 domain on its amino terminus. Recent studies have suggested that p66- Shc can act as a feedback down-regulator of growth factor signaling to Erki 12 and c-fos, and also can act as an apoptotic sensitizer to oxidative stress. In many cell lines, the functions of p66-Shc require phosphorylation in serine-36 of its unique CH2 domain. Our laboratory has reported a strong negative correlation between the levels of tyrosine phosphorylated p52-Shc and the levels of p66-Shc in cell lines derived from human breast cancers.