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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2014
Journal
Proc Natl Acad Sci U S A
Volume
111
Issue
3
Pages
1102-7
Date Published
2014 Jan 21
ISSN
1091-6490
URL
DOI
10.1073/pnas.1311909111
PubMed ID
24385586
PubMed Central ID
PMC3903232
Links
Grant list
U54 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