The c-erbB2 (or HER-2, neu) gene encodes a l85-kDa transmembrane glycoprotein (pl85), which is a growth factor receptor of the epidermal growth factor receptor (EGF-r) family. Our previous studies demonstrated that c-erbB2 overexpression can enhance metastatic potential and confer increased chemoresistance to breast cancer cells, thereby leading to poor clinical outcome in breast cancer patients. Our recent studies demonstrated that overexpression of the c-erbB2 gene can protect human breast cancer cells from apoptosis induced by the chemotherapeutic agent Taxol, by radiation, or by serum starvation. These new findings provided an explanation on c-erbB2- mediated chemoresistance of breast cancer cells and poor prognosis of the patients. Therefore, it is very important to understand the mechanisms of antiapoptosis by c-erbB2. However, little is known about the molecular mechanisms of antiapoptosis by c-erbB2 overexpression in breast cancer cells. Since the pl85c-erbB2 is a receptor tyrosine kinase (RTK), we hypothesize that c- erbB2 overexpression may enhance the RTK signaling capacity that activates downstream effectors for antiapoptotic signaling. In this application, I will study: (1) Identify structural requirements for c-erbB2 receptor antiapoptosis signaling. (2) Investigate the involvement of c-erbB2 immediate-downstream signaling (Shc-(3rb2-Ras or PI3K) in antiapoptosis.
