Role of Gab2 in mammary tumorigenesis and metastasis
Role of Gab2 in mammary tumorigenesis and metastasis
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DOI：
10.1038/sj.onc.1210315
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Feng, G-S
中科院分区：
文献类型：
--
作者：
Ke, Y.;Wu, D.;Feng, G-S
在原发性人乳腺癌细胞和细胞系中检测到适配器/支架蛋白Gab2的过表达，尽管其功能意义重大。乳腺癌的发生机制尚不完全清楚。在这里，我们发现Gab2在促进乳腺肿瘤转移中是必需的。虽然在Neu （ErbB-2）致癌基因诱导的乳腺肿瘤中Gab2表达水平升高，但小鼠中Gab2的纯合缺失对Neu诱导的乳腺肿瘤的发生只有适度的影响。值得注意的是，消融Gab2严重抑制了肺转移。缺乏gab2的癌细胞表现出正常的Akt活性，其体外增殖率与对照细胞相似。然而，Gab2（-/-）癌细胞表现出迁移减少和Erk激活受损，并且通过将Gab2重新引入Gab2（-/-）细胞来修复这些缺陷。这些。研究结果提示，尽管Gab2过表达可能赋予肿瘤细胞生长优势，但Gab2在乳腺肿瘤发生/生长中的功能需求可能是多余的，Gab2在促进乳腺肿瘤转移中可能具有突出作用。
Overexpression of the adaptor/scaffolding protein Gab2 has been detected in primary human breast cancer cells and cell lines, although its functional signifi. cance in breast carcinogenesis is not fully understood. Here, we show a requirement for Gab2 in promoting mammary tumor metastasis. Although Gab2 expression levels were elevated in mammary tumors induced by the Neu (ErbB-2) oncogene, homozygous deletion of Gab2 in mice had only a modest effect on the initiation of Neu-induced mammary tumors. Notably, ablation of Gab2 severely suppressed lung metastasis. Gab2-deficient cancer cells displayed normal Akt activities, and their proliferative rate in vitro was similar to control cells. However, Gab2(-/-) cancer cells exhibited decreased migration and impaired Erk activation, and the defects were rescued by re-introduction of Gab2 into Gab2(-/-) cells. These. ndings suggest that although Gab2 overexpression may confer growth advantage to tumor cells, the functional requirement for Gab2 in mammary tumor initiation/growth may be dispensable, and that Gab2 may have a prominent role in promoting mammary tumor metastasis.