Network Interaction of erbB, neu-erbB2, erbB3, erbB4, in the Biological Responseto NDF/Neuregulins

摘要

The gene encoding the neu/erB-2/HER-2 receptor tyrosine kinase is one of a smallnumber of genes known to be altered in human breast and ovarian carcinoma. It is amplified and/or over expressed in approximately one-fourth of these cancers. With its probable role in etiology, and expression at the cell surface, neu has great potential as a prognostic indicator and therapeutic target. Efforts to exploit this receptor in the clinical arena have been impeded by the failure to consider regulation of neu by hormones and co-receptors. This has been complicated by the fact that at least seven different peptide hormones, epidermal growth factor (EGF), transforming growth factor-alpha, amphiregulin, betacellulin, heparin-binding EGF-like growth factor, epiregulin, and the diverse neuregulins are all able to activate neu. They work by binding to the co-receptors EGF receptor, erB-3 and erB-4, which then dimerize with neu. Work by this laboratory has shown that each one of these factors activates a different constellation of receptors, leading to a great diversity of possible responses. Moreover, the coupling of cellular responses to each factor is determined by the subset of receptors expressed in each tissue. Thus in order to interpret the function of any one of the factors or receptors, including neu, it is essential to consider the influences provided by the entire set.