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

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. H...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-01, Vol.111 (3), p.1102-1107
Main Authors: Dunn, Gavin P., Cheung, Hiu Wing, Agarwalla, Pankaj K., Thomas, Sapana, Zektser, Yulia, Karst, Alison M., Boehm, Jesse S., Weir, Barbara A., Berlin, Aaron M., Zou, Lihua, Getz, Gad, Liu, Joyce F., Hirsch, Michelle, Vazquez, Francisca, Root, David E., Beroukhim, Rameen, Drapkin, Ronny, Hahn, William C.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Biological Sciences
Breast cancer
Cancer
Cell Line, Tumor
Cell lines
Cell Proliferation
Cell Transformation, Neoplastic
Epithelial cells
Female
Gene Amplification
Gene Expression Regulation, Neoplastic
Genes
Genetics
Genomics
Humans
Kinases
Mice
Mice, Nude
Neoplasm Transplantation
Oligonucleotide Array Sequence Analysis
Oncogenes
Open Reading Frames
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Proteins
Signal Transduction
Transformed cell line
Tumor cell line
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1311909111