The HER2/c-erbB-2 gene encodes the epidermal growth factor receptorlike human homolog of the rat neu oncogene. Amplification of this gene in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain cancer patients. We show here that a monoclonal antibody directed against the extraceUlular domain of p185HER2 specifically inhibits the growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2 gene product and prevents HER2/c-erbB-2-transformed NIH 3T3 cells from forming colonies in soft agar. Furthermore, resistance to the cytotoxic effect of tumor necrosis factor alpha, which has been shown to be a consequence of HER2/c-erbB-2 overexpression, is significantly reduced in the presence of this antibody.HER21c-erbB-2, the human homolog of the rat protooncogene neu (4, 34), encodes a 1,255-amino-acid glycoprotein with extensive homology to the human epidermal growth factor (EGF) receptor (4,21,33,34,42). The HER21c-erbB-2 gene product, p185HER2, has all of the structural features and many of the functional properties of subclass I growth factor receptors (reviewed in references 43 and 44), including cell surface location and an intrinsic tyrosine kinase activity. However, the ligand for this putative growth factor receptor has not yet been identified.Amplification of the HER21c-erbB-2 gene has been found in human salivary gland and gastric tumor-derived cell lines (13, 34), as well as in mammary gland carcinomas (21,22,40,42). Slamon et al. (35) surveyed 189 primary breast adenocarcinomas and determined that the HER21c-erbB-2 gene was amplified in about 30% of the cases. Most importantly, HER21c-erbB-2 amplification was correlated with a negative prognosis and high probability of relapse. Similar although less frequent amplification of the HER21c-erbB-2 gene has been reported for gastric and colon adenocarcinomas (45,46). Experiments with NIH 3T3 cells also suggest a direct role for the overexpressed, structurally unaltered HER21 c-erbB-2 gene product p185HER2 in neoplastic transformation. High levels of HER21c-erbB-2 gene expression attained by coamplification of the introduced gene with dihydrofolate reductase by methotrexate selection (18) or by using a strong promoter (6) was shown to transform NIH 3T3 fibroblasts.Only cells with high levels of pl85HER2 are transformed, i.e., have an altered morphology, are anchorage independent, and will form tumors in athymic mice.
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