2885

GRB2

growth factor receptor-bound protein 2;GRB2;growth factor receptor-bound protein 2

HT027|SH2/SH3 adapter GRB2|abundant SRC homology|epidermal growth factor receptor-binding protein GRB2|growth factor receptor-bound protein 3|protein Ash

17q24-q25

protein-coding

metastasis-associated genomic alterations have been recognized to play a critical role in tumor metastasis. Primary and metastatic tumor cells in mice and tumors in a patient were studied by cDNA array analysis. Selected genes were determined by RT-PCR and immunohistochemistry. pathways on changed genes were statistically analyzed. The function of Grb2 was determined by in vitro wound assay. Nodal metastatic cells had a stronger ability of growth and metastasis than primary tumor cells. A total of 376 genes showed a different expression between primary and metastatic cells. The expression of Grb2 and genes in the Grb2-mediated pathways was significantly elevated in the metastases. Elevated levels of Grb2 expression in metastases were related to the distant metastasis of colorectal carcinoma. Blocking the Grb2-SH2 domain signaling transduction inhibited cell motility. metastasis-associated genes identified by cDNA and tissue microarrays provide potentially valuable information on the metastasis of colorectal tumors. Overexpression of Grb2 may contribute to tumor growth, invasiveness and metastasis.

metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain-binding, C90, blocks growth factor-driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process.