Basic science of HER-2/neu: a review.

ABSTRACT

The HER-2/neu (also known as c-erbB-2) oncogene is the second member of the epidermal growth factor receptor family. It is overexpressed in many different types of human cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER-2/neu in breast cancer has been associated with poor overall survival and has been shown preclinically to enhance malignancy and the metastatic phenotypes. Although discrepancies exist between different studies, HER-2/ neu overexpression seems to induce chemoresistance in certain experimental conditions. Many studies have convincingly shown that repression of HER-2/neu suppresses the malignant phenotypes of HER-2/neu-overexpressing cancer cells. These findings strongly suggest that HER-2/neu may serve as an excellent target for developing anticancer agents specific for HER-2/neu-overexpressing cancer cells. HER-2/neu-encoded p185 protein is a receptor tyrosine kinase that can be associated with multiple signal transduction pathways. However, it is not yet clear how a specific signal pathway may correspond to a specific biological response. This report reviews basic information on signal transduction of HER-2/neu receptor tyrosine kinase and summarizes our approaches to targeting HER-2/neu-overexpressing cancer cells. The HER-2/neu promoter was targeted using cationic liposomes or an adenovirus vector to deliver the adenovirus-5 EIA gene products and a nontransformed mutant of the SV40 large T antigen into the tumor-bearing mice. This resulted in suppression of the tumor growth and prolongation of survival. For repressing the function of HER-2/neu we used emodin, a tyrosine kinase inhibitor. This agent can inhibit the tyrosine kinase activity of HER-2/neu and preferentially block the growth of the HER-2/neu-overexpressing human breast cancer cells in tissue culture as well as in nude mice.