Hudziak R M, Lewis G D, Shalaby M R, Eessalu T E, Aggarwal B B, Ullrich A, Shepard H M
Department of Developmental Biology, Genentech, Inc., San Francisco, CA 94080.
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5102-6. doi: 10.1073/pnas.85.14.5102.
Functional characterization of oncogene products that induce cellular transformation has progressed rapidly in recent years. However, less is known about the mechanism(s) by which the transformed cells may escape destruction by host immune defenses and form tumors. A recently described oncogene that has an important association with aggressive human breast carcinoma is "HER2," for human epidermal growth factor receptor 2. The oncogene has also been called NGL and human c-erbB-2 (ERBB2). In this paper we show that amplification of HER2 oncogene expression can induce resistance of NIH 3T3 cells to the cytotoxic effects of recombinant tumor necrosis factor alpha (rTNF-alpha) or macrophages. Resistance is accompanied by an increased dissociation constant for rTNF-alpha binding to high-affinity receptors on the HER2-transformed NIH 3T3 cells. The resistance phenotype is independent of transformation since NIH 3T3 cells transformed by the activated human homologue of the Harvey-ras oncogene (HRAS) retain high-affinity binding sites for rTNF-alpha as well as sensitivity to its cytotoxic effects. These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms.
近年来，对诱导细胞转化的癌基因产物的功能特性研究进展迅速。然而，对于转化细胞如何逃避宿主免疫防御的破坏并形成肿瘤的机制，我们却知之甚少。一种最近被描述的、与侵袭性人类乳腺癌密切相关的癌基因是“HER2”，即人类表皮生长因子受体2。该癌基因也被称为NGL和人类c-erbB-2（ERBB2）。在本文中，我们表明HER2癌基因表达的扩增可诱导NIH 3T3细胞对重组肿瘤坏死因子α（rTNF-α）或巨噬细胞的细胞毒性作用产生抗性。抗性伴随着rTNF-α与HER2转化的NIH 3T3细胞上高亲和力受体结合的解离常数增加。由于由哈维 - 拉斯癌基因（HRAS）的活化人类同源物转化的NIH 3T3细胞保留了对rTNF-α的高亲和力结合位点以及对其细胞毒性作用的敏感性，所以抗性表型与转化无关。这些结果表明，HER2可能通过诱导肿瘤细胞对宿主防御机制的抗性来增强肿瘤发生。
