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Carcinogenesis Advance Access published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm221
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

GRB-7 Facilitates HER-2/Neu Mediated Signal Transduction and Tumor Formation

Tao Bai and Shiuh-Wen Luoh

Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland VA Medical Center, Portland OR 97239

Requests for reprints: Shiuh-Wen Luoh MD. PhD., R&D 47, Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, 503-220-8262 ext 54255 (Tel), 503-402-2817 (Fax), 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 immuno-blotting 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. Knock down 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 PLC-{gamma}-1 and recruitment of PLC-{gamma}-1 to HER-2/Neu protein molecule. Activation of downstream PKC pathway is evidenced by increase in the phosphorylation of a common PKC 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.

Received July 13, 2007; revised September 17, 2007; accepted September 21, 2007.


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