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Focal amplification and oncogene dependency of GAB2 in breast cancer

M Bocanegra1, A Bergamaschi, Y H Kim

  • 1Department of Pathology, Stanford University, Stanford, CA 94305-5176, USA.

Oncogene
|November 3, 2009
PubMed

Insights

Focal amplification of GRB2-associated binding protein 2 (GAB2) drives breast cancer by promoting cell proliferation, survival, and invasion. GAB2 amplification is independent of CCND1 and may represent a new therapeutic target.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Chromosome 11q amplifications are common in breast cancer, potentially involving multiple driver oncogenes beyond CCND1.
  • GRB2-associated binding protein 2 (GAB2), a scaffolding adapter protein, plays a role in ErbB signaling and has been linked to breast cancer progression in preclinical models.
  • The amplification status and specific function of GAB2 in human breast cancer remain largely uncharacterized.

Purpose of the Study:

  • To investigate the amplification status and functional role of GAB2 in breast cancer.
  • To determine if GAB2 amplification is an independent event and its potential as a driver oncogene.
  • To explore the downstream signaling pathways affected by GAB2 in breast cancer cells.

Main Methods:

  • Genomic profiling of 172 breast tumors to identify GAB2 amplification.
  • Fluorescence in situ hybridization (FISH) for validation in an independent cohort of 210 breast tumors.
  • Small interfering RNA (siRNA)-mediated knockdown of GAB2 in amplified breast cancer cell lines (SUM52, SUM44PE, MDA468) and an ERBB2-amplified cell line (BT474).
  • Assessment of cell proliferation, cell-cycle progression, survival, and invasion assays.
  • Analysis of downstream signaling pathways including PI3K and MAPK.

Main Results:

  • Focal amplification of GAB2 at 11q14.1 was identified, occurring independently of CCND1 amplification (11q13.2).
  • GAB2 knockdown in amplified breast cancer cell lines demonstrated a dependency on GAB2 for proliferation, cell-cycle progression, survival, and invasion.
  • Altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways were observed following GAB2 knockdown.
  • GAB2 knockdown also reduced proliferation and survival in an ERBB2-amplified cell line, suggesting a potential role downstream of ERBB2.

Conclusions:

  • Focal amplification of GAB2 is implicated in breast carcinogenesis and acts as a driver oncogene.
  • Scaffolding adapter proteins like GAB2 play a significant oncogenic role in breast cancer.
  • GAB2 represents a potential new therapeutic target for breast cancer treatment.

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