Carcinogenesis Advance Access originally published online on October 4, 2007
Carcinogenesis 2008 29(3):473-479; doi:10.1093/carcin/bgm221
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GRB-7 facilitates HER-2/Neu-mediated signal transduction and tumor formation
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland VA Medical Center, Portland, OR 97239, USA
* To whom correspondence should be addressed. Fax: +1 503 402 2817; Email: luohs{at}ohsu.edu
Growth factor receptor-bound protein-7 (GRB-7), an adaptor molecule, can interact with multiple signal transduction molecules. GRB-7 is amplified concurrently with HER-2/Neu in most, if not all, of breast cancer with chromosome 17q11–21 amplification. GRB-7 gene amplification is associated with RNA over-expression. We show GRB-7 protein is over-expressed by immunoblotting in breast cancer cell lines and primary breast tumors with HER-2/Neu protein over-expression. Over-expression of GRB-7 in MCF-7 breast cancer cells that over-express HER-2/Neu leads to activation of tyrosine phosphorylation of HER-2/Neu. Knockdown of GRB-7 expression in SKBR-3 breast cancer cells with naturally occurring HER-2/Neu gene amplification decreases tyrosine phosphorylation of HER-2/Neu. Activation of HER-2/Neu phosphorylation is associated with increase in tyrosine phosphorylation of phosphoinositide-specific lipase C-
-1 (PLC--1) and recruitment of PLC--1 to HER-2/Neu protein molecule. Activation of downstream protein kinase C (PKC) pathway is evidenced by increase in the phosphorylation of a common PKC substrate—myristoylated alanine-rich protein kinase C substrate (MARCKS). In addition, over-expression of GRB-7 in MCF-7 breast cancer cells that over-express HER-2/Neu leads to activation of AKT phosphorylation. Knockdown of GRB-7 expression in MB-453 and SKBR-3 breast cancer cells results in decrease in AKT phosphorylation. GRB-7 over-expression therefore facilitates activation of phosphorylation of HER-2/Neu and AKT in breast cancer cells with HER-2/Neu over-expression. GRB-7 over-expression in MCF-7 cells over-expressing HER-2/Neu leads to morphologic change of cells and promotes tumor xenograft growth in nude mice. GRB-7 over-expression therefore plays pivotal roles in activating signal transduction and promoting tumor growth in breast cancer cells with chromosome 17q11–21 amplification.
Abbreviations: GRB-7, growth factor receptor-bound protein-7; MARCKS, myristoylated alanine-rich protein kinase C substrate; siRNA, small interfering RNA
Received July 13, 2007; revised September 17, 2007; accepted September 21, 2007.
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