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Focal amplification and oncogene dependency of GAB2 in breast cancer

Oncogene volume 29, pages 774–779 (2010)Cite this article

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.

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Acknowledgements

We thank the Stanford Functional Genomics Facility for microarray manufacture, the Stanford Microarray Database for database support and members of the Pollack lab for helpful discussion. This work was supported in part by grants from the National Institutes of Health, CA97139 (JRP), CA09302 and CA130172 (MB); the Department of Defense Breast Cancer Research Program, BC073467 (MB); the California Breast Cancer Research Program, 8KB-0135 (JRP) and 11IB-0175 (SSJ); the Norwegian Research Council, NFR, 155218/300 (ALBD); and the Korea Health 21 R&D Project, Ministry of Health & Welfare ROK, 01-PJ3-PG6-01GN07-0004 (WH and D-YN). AB was during this work a fellow of The Norwegian Cancer Society. DGH is a Michael Smith Foundation for Health Research Scholar. Funding for the thermomechanical analysis was provided in part by an unrestricted educational grant from Sanofi-aventis, Canada.

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Authors and Affiliations

  1. Department of Pathology, Stanford University, Stanford, CA, USA

    M Bocanegra, A Bergamaschi, Y H Kim, J Kao & J R Pollack

  2. Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    A Bergamaschi, A Langerød & A -L Børresen-Dale

  3. Department of Pathology, University of British Columbia, and British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    M A Miller, A B Rajput & D G Huntsman

  4. Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

    W Han & D -Y Noh

  5. Department of Surgery, Stanford University, Stanford, CA, USA

    S S Jeffrey

  6. Faculty Division, The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway

    A -L Børresen-Dale

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  1. M Bocanegra
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  2. A Bergamaschi
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  3. Y H Kim
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  4. M A Miller
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  6. J Kao
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  7. A Langerød
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  8. W Han
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  9. D -Y Noh
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  10. S S Jeffrey
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  11. D G Huntsman
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  13. J R Pollack
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Correspondence to J R Pollack.

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Bocanegra, M., Bergamaschi, A., Kim, Y. et al. Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene 29, 774–779 (2010). https://doi.org/10.1038/onc.2009.364

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  • DOI: https://doi.org/10.1038/onc.2009.364

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