Nature Medicine
- 12, 114 - 121 (2005)
Published online: 20 December 2005; | doi:10.1038/nm1341
A role for the scaffolding adapter GAB2 in breast cancerMohamed Bentires-Alj1, 2, Susana G Gil1, Richard Chan1, Zhigang C Wang3, Yongping Wang1, Naoko Imanaka1, Lyndsay N Harris4, Andrea Richardson5, Benjamin G Neel1 & Haihua Gu11
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, NRB 1030, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. 2
Laboratory of Medical Chemistry and Human Genetics, Center for Biomedical Integrative Genoproteomics, University of Liège, Pathologie B23, Domaine du Sart-Tilman 4000 Liège, Belgium. 3
Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. 4
Department of Adult Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. 5
Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
Correspondence should be addressed to Haihua Gu hgu@bidmc.harvard.edu or Mohamed Bentires-Alj mbentire@bidmc.harvard.edu The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.
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