New insights into anti-HER-2 receptor monoclonal antibody research

Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB-2 encodes the HER-2 receptor (also known as c-erbB-2 or c-neu) that is overexpressed, amplified, or both in a number of human malignancies including breast, ovarian, colon, lung, prostate, and cervical cancers. In addition to deregulation of cell-surface HER receptors, cancer cells often show excessive activation and/or nonattenuation of growth factor--inducible signaling components, as well as their downstream transcription factors. Current approaches to target HER-2 pathways include downregulation of HER-2 by the adenovirus 5E1A, antisense phosphothionate oligonucleotides, ribozyme, and targeting tyrosine kinase using specific inhibitors. Because growth factors regulate the proliferation of cancer cells by activating receptors on the surface of cells, one obvious approach to control cell proliferation is to interfere with the growth factor receptor-mediated autocrine/ paracrine growth stimulation by antireceptor-blocking monoclonal antibodies. Therefore, a large number of scientists are attempting to control the growth of cancer cells using agents that inhibit one or more of the above steps of growth factor action. Recently completed clinical trials established the usefulness of a humanized form of 4DS monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), against some forms of breast tumors overexpressing HER-2 receptors. Using in vitro models, recent studies have shown that HER-2 overexpression may not be a prerequisite for invasion of breast cancer cells, as HER-2 activation by heregulin, which binds to HER-3 or HER-4 and transphosphorylates HER in noninvasive breast cancer cells, could lead to increased motility, enhanced gelatinolytic activity, and invasion. Furthermore, these ligand-driven phenotypic changes were completely suppressed by trastuzumab, which also blocked interactions between HER-2 and HER-3 receptors in heregulin-treated breast cancer cells, and inhibited the phosphatidylinositol-3' kinase-dependent pathway, but not the mitogen-activated protein kinase pathway. These phenotypic effects of anti-HER-2 monoclonal antibody are of special interest, because they point to potential therapeutic effects of trastuzumab in inhibiting the invasion and metastasis of breast cancer with low receptor expression.