THE C-ERB-2 PROTEIN IN ONCOGENESIS - MOLECULAR-STRUCTURE TO MOLECULAREPIDEMIOLOGY

The c-erbB-2 (HER-2, neu) oncogene has been implicated frequently in m any human tumors. This oncogene codes for a 185-kDa protein that funct ions as a transmembrane growth factor receptor. Overexpression of the normal protein or point mutations in the transmembrane domain of the p rotein have been shown to have a transforming effect. Molecular struct ure studies of the transmembrane domain provide a plausible explanatio n for this transforming effect in both cases and relate this to the pr ocess of receptor dimerization in the membrane, degradation of the pro tein with release of the extracellular domain (ECD) into the extracell ular environment, and aberrant signal transduction. The release of the ECD into the extracellular environment provides a potential biomarker for the study of signal transduction at the molecular level in vivo. The ECD can be quantitated immunologically in the serum of individuals with cancers associated with p185 overexpression and in individuals a t risk for the development of such cancers and can be used to distingu ish these individuals from normal, healthy controls. Identification of such individuals by their serum ECD levels combined with specific che motherapeutic/chemoprophylactic interventions could allow for improvem ent treatment and prevention of c-erbB-2-related cancers.