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

Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1102-7. doi: 10.1073/pnas.1311909111. Epub 2014 Jan 2.

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.

Keywords: ORF; functional genomics; open reading frame.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • 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 / genetics*
  • Ovarian Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB2 protein, human
  • Phosphatidylinositol 3-Kinases