1. ¹Cancer Center, Burnham Institute for Medical Research, La Jolla, CA, USA
2. ²Molecular Oncology Group, Royal Victoria Hospital, Montreal, Quebec, Canada

Correspondence: Professor G-S Feng, Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA. E-mail: gfeng@burnham.org

Received 27 July 2006; Revised 28 November 2006; Accepted 1 January 2007; Published online 19 February 2007.

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.