Abstract
Overexpression of the adaptor/scaffolding protein Gab2 has been detected in primary human breast cancer cells and cell lines, although its functional significance 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 findings 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.
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Acknowledgements
We thank Dr R Cardiff at UC Davis for pathological examination of tumor metastasis in lung, Dr DH Yu for work done in the early stages of the Gab2 gene targeting project, X Xiao (Aceabio sciences Inc) for helpful discussion and generosity in providing RT-CES biosensor and also J Zhu for technical assistance, Dr D Schlaepfer at Scripps for anti-FAK antibody. This work was supported by NIH grants (HL66208, CA78606, CA102583). YK is a recipient of a postdoctoral fellowship (9FB-0170) from the California Breast Cancer Research Program. WJM is supported by the CRC Chair in Molecular Oncology.
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Ke, Y., Wu, D., Princen, F. et al. Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 26, 4951–4960 (2007). https://doi.org/10.1038/sj.onc.1210315
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DOI: https://doi.org/10.1038/sj.onc.1210315
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