1. ¹Department of Pathology, Stanford University, Stanford, CA, USA
2. ²Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
3. ³Department of Pathology, University of British Columbia, and British Columbia Cancer Agency, Vancouver, British Columbia, Canada
4. ⁴Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
5. ⁵Department of Surgery, Stanford University, Stanford, CA, USA
6. ⁶Faculty Division, The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway

Correspondence: Dr JR Pollack, Department of Pathology, Stanford University School of Medicine, CCSR-3245A, 269 Campus Drive, Stanford, CA 94305-5176, USA. E-mail: pollack1@stanford.edu

Received 25 March 2009; Revised 29 July 2009; Accepted 27 August 2009; Published online 2 November 2009.

Abstract

DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.