Role of Gab2 in mammary tumorigenesis and metastasis.
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.
Ke
Y
Y
Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Wu
D
D
Princen
F
F
Nguyen
T
T
Pang
Y
Y
Lesperance
J
J
Muller
W J
WJ
Oshima
R G
RG
Feng
G-S
GS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018734:Genes, erbB-2; D008175:Lung Neoplasms / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D048049:Extracellular Signal-Regulated MAP Kinases