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.