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Focal amplification and oncogene dependency of GAB2 in breast cancer

Cited 55 time in Web of Science Cited 57 time in Scopus
Issue Date
2010-02-04
Publisher
NATURE PUBLISHING GROUP
Citation
ONCOGENE; Vol.29 5; 774-779
Keywords
GAB2genomic profilingbreast canceroncogene dependencyarray-based comparative genomic hybridizationDNA amplification
Abstract
DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention. Oncogene (2010) 29, 774-779; doi: 10.1038/onc.2009.364; published online 2 November 2009
ISSN
0950-9232
Language
English
URI
https://hdl.handle.net/10371/77950
DOI
https://doi.org/10.1038/onc.2009.364
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College of Medicine/School of Medicine (의과대학/대학원)Surgery (외과학전공)Journal Papers (저널논문_외과학전공)
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