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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1311909111

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.

Publication TypeJournal Article
Year of Publication2014
AuthorsDunn, GP, Cheung, HWing, Agarwalla, PK, Thomas, S, Zektser, Y, Karst, AM, Boehm, JS, Weir, BA, Berlin, AM, Zou, L, Getz, G, Liu, JF, Hirsch, M, Vazquez, F, Root, DE, Beroukhim, R, Drapkin, R, Hahn, WC
JournalProc Natl Acad Sci U S A
Volume111
Issue3
Pages1102-7
Date Published2014 Jan 21
ISSN1091-6490
KeywordsAdaptor Proteins, Signal Transducing, Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Genomics, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Oligonucleotide Array Sequence Analysis, Open Reading Frames, Ovarian Neoplasms, Phosphatidylinositol 3-Kinases, Signal Transduction
Abstract

High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=24385586
DOI10.1073/pnas.1311909111
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24385586?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID24385586
PubMed Central IDPMC3903232
Grant ListU54 CA143798 / CA / NCI NIH HHS / United States
U01 CA152990 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States