Chazin V R, Kaleko M, Miller A D, Slamon D J
Department of Medicine, University of California, Los Angeles.
Oncogene. 1992 Sep;7(9):1859-66.
Amplification of the HER-2 (c-erbB-2) gene and overexpression of the p185HER-2 gene product is found in approximately one-third of primary human breast and ovarian cancers and is associated with a poor clinical outcome of early relapse and death. The HER-2 gene encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity. Wild-type human HER-2 has been shown to act as a potent oncogene when over-expressed in mouse fibroblasts. Recent data suggest that the mechanism by which HER-2 mediates transformation requires the interaction of the epidermal growth factor (EGF) receptor. To test whether overexpression of normal human HER-2 can transform cells independently of the EGF receptor, we have introduced multiple copies of HER-2 into the EGF receptor-negative cell line, NR6, and have performed assays for both transformation and tumorigenicity. Engineered NR6 cells that overexpress the HER-2 gene product display a highly transformed and tumorigenic phenotype as compared with control cells. Additionally, a monoclonal antibody to the extracellular domain of the HER-2 receptor is able to inhibit the proliferation of the overexpressing cells in vitro as well as tumor growth in vivo. This study provides clear evidence that HER-2-mediated transformation can be achieved independently of the EGF receptor.
在大约三分之一的原发性人类乳腺癌和卵巢癌中发现HER-2（c-erbB-2）基因扩增和p185HER-2基因产物过表达，且这与早期复发和死亡的不良临床结局相关。HER-2基因编码一种具有内在酪氨酸激酶活性的细胞表面生长因子受体。野生型人类HER-2在小鼠成纤维细胞中过表达时已被证明可作为一种强效癌基因。最近的数据表明，HER-2介导转化的机制需要表皮生长因子（EGF）受体的相互作用。为了测试正常人HER-2的过表达是否能独立于EGF受体转化细胞，我们将多个HER-2拷贝导入EGF受体阴性细胞系NR6，并进行了转化和致瘤性检测。与对照细胞相比，过表达HER-2基因产物的工程化NR6细胞表现出高度转化和致瘤的表型。此外，一种针对HER-2受体细胞外结构域的单克隆抗体能够在体外抑制过表达细胞的增殖以及在体内抑制肿瘤生长。这项研究提供了明确的证据，即HER-2介导的转化可以独立于EGF受体实现。
