A role for the scaffolding adapter GAB2 in breast cancer


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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Figure 1: Effects of Gab2 overexpression alone or in combination with other genes on MCF10A cells in three-dimensional cultures.
Figure 2: Gab2 cooperates with Neu to form invasive multiacinar structures.
Figure 3: Gab2 activates the Erk pathway through Shp2 in three-dimensional cultures.
Figure 4: The level of Gab2 expression is crucial for NeuNT-evoked mammary tumorigenesis in mice.
Figure 5: GAB2 is amplified and overexpressed in human breast cancer.


  1. 1

    Bissell, M.J. & Radisky, D. Putting tumours in context. Nat. Rev. Cancer 1, 46–54 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Schlessinger, J. & Lemmon, M.A. SH2 and PTB domains in tyrosine kinase signaling. Sci. STKE 191, RE12 (2003).

    Google Scholar 

  3. 3

    Liu, Y. & Rohrschneider, L.R. The gift of Gab. FEBS Lett. 515, 1–7 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Gu, H. & Neel, B.G. The “Gab” in signal transduction. Trends Cell Biol. 13, 122–130 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Gu, H. et al. Essential role for Gab2 in the allergic response. Nature 412, 186–190 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Gu, H., Botelho, R.J., Yu, M., Grinstein, S. & Neel, B.G. Critical role for scaffolding adapter Gab2 in Fc gamma R-mediated phagocytosis. J. Cell Biol. 161, 1151–1161 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Kong, M., Mounier, C., Dumas, V. & Posner, B.I. Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2. J. Biol. Chem. 278, 5837–5844 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Nishida, K. et al. Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. Blood 99, 1866–1869 (2002).

    Article  Google Scholar 

  9. 9

    Wada, T. et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat. Med. 11, 394–399 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Sattler, M. et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1, 479–492 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Ischenko, I., Petrenko, O., Gu, H. & Hayman, M.J. Scaffolding protein Gab2 mediates fibroblast transformation by the SEA tyrosine kinase. Oncogene 22, 6311–6318 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Feng, G.S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp. Cell Res. 253, 47–54 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Neel, B.G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 34, 148–150 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Bentires-Alj, M. et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816–8820 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Mohi, M.G. et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7, 179–191 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Daly, R.J. et al. The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. Oncogene 21, 5175–5181 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Yamada, K., Nishida, K., Hibi, M., Hirano, T. & Matsuda, Y. Comparative FISH mapping of Gab1 and Gab2 genes in human, mouse and rat. Cytogenet. Cell Genet. 94, 39–42 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Ormandy, C.J., Musgrove, E.A., Hui, R., Daly, R.J. & Sutherland, R.L. Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res. Treat. 78, 323–335 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Bekri, S. et al. Detailed map of a region commonly amplified at 11q13 → q14 in human breast carcinoma. Cytogenet. Cell Genet. 79, 125–131 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Slamon, D.J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Muller, W.J., Sinn, E., Pattengale, P.K., Wallace, R. & Leder, P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115 (1988).

    CAS  Article  Google Scholar 

  24. 24

    Bouchard, L., Lamarre, L., Tremblay, P.J. & Jolicoeur, P. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57, 931–936 (1989).

    CAS  Article  Google Scholar 

  25. 25

    Debnath, J. et al. The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell 111, 29–40 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Mills, K.R., Reginato, M., Debnath, J., Queenan, B. & Brugge, J.S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl. Acad. Sci. USA 101, 3438–3443 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Dankort, D. et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol. Cell. Biol. 21, 1540–1551 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Dankort, D., Jeyabalan, N., Jones, N., Dumont, D.J. & Muller, W.J. Multiple ErbB-2/Neu phosphorylation sites mediate transformation through distinct effector proteins. J. Biol. Chem. 276, 38921–38928 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 (1993).

    CAS  Article  Google Scholar 

  30. 30

    Lock, L.S., Royal, I., Naujokas, M.A. & Park, M. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J. Biol. Chem. 275, 31536–31545 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Muthuswamy, S.K., Li, D., Lelievre, S., Bissell, M.J. & Brugge, J.S. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat. Cell Biol. 3, 785–792 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Matros, E. et al. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res. Treat. 91, 179–186 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Richardson, A. et al. Specific contributions by X chromosomal abnormalities to basal-like, human breast cancer. Cancer Cell (in the press).

  35. 35

    Shaulian, E. & Karin, M. AP-1 in cell proliferation and survival. Oncogene 20, 2390–2400 (2001).

    CAS  Article  Google Scholar 

  36. 36

    Aronheim, A. et al. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell 78, 949–961 (1994).

    CAS  Article  Google Scholar 

  37. 37

    Chan, R.J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Balasenthil, S. et al. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J. Biol. Chem. 279, 1422–1428 (2004).

    CAS  Article  Google Scholar 

  39. 39

    Reyal, F. et al. Visualizing chromosomes as transcriptome correlation maps: evidence of chromosomal domains containing co-expressed genes–a study of 130 invasive ductal breast carcinomas. Cancer Res. 65, 1376–1383 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Wang, R.A., Mazumdar, A., Vadlamudi, R.K. & Kumar, R. P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J. 21, 5437–5447 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Bautista, S. & Theillet, C. CCND1 and FGFR1 coamplification results in the colocalization of 11q13 and 8p12 sequences in breast tumor nuclei. Genes Chromosom. Cancer 22, 268–277 (1998).

    CAS  Article  Google Scholar 

  42. 42

    Huang, E. et al. Gene expression predictors of breast cancer outcomes. Lancet 361, 1590–1596 (2003).

    CAS  Article  Google Scholar 

  43. 43

    Gu, H., Pratt, J.C., Burakoff, S.J. & Neel, B.G. Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation. Mol. Cell 2, 729–740 (1998).

    CAS  Article  Google Scholar 

  44. 44

    Gu, H. et al. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol. Cell. Biol. 20, 7109–7120 (2000).

    CAS  Article  Google Scholar 

  45. 45

    Debnath, J., Muthuswamy, S.K. & Brugge, J.S. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256–268 (2003).

    CAS  Article  Google Scholar 

  46. 46

    Brummelkamp, T.R., Bernards, R. & Agami, R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243–247 (2002).

    CAS  Article  Google Scholar 

  47. 47

    Gil-Henn, H. & Elson, A. Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J. Biol. Chem. 278, 15579–15586 (2003).

    CAS  Article  Google Scholar 

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We thank J. Brugge (Harvard Medical School) and members of her laboratory for help with the MCF10A system, R. Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for histological analyses, J.Q. Shen for technical assistance, V.M. Weaver (University of Pennsylvania), and members of the Neel lab for advice and discussions, and various colleagues for reagents. This work was supported by US National Institutes of Health (NIH) grant DK50693 and Department of Defense (DOD) grant DAMD170310284 (to B.G.N.) and NIH grant AI 51612 (to H.G.). M.B.-A. was supported by fellowships from International Agency for Research on Cancer (World Health Organization), European Molecular Biology Organization and the DOD Breast Cancer Research Program, and is a Research Assistant at the National Fund for Scientific Research (FNRS, Belgium). Z.C.W. and A.R. were partially supported by the National Cancer Institute Special Program of Research Excellence in Breast Cancer at the Beth Israel Deaconess Medical Center and Brigham and Women's Hospital, Boston, and R.C. by a postdoctoral fellowship from the Susan Komen Breast Cancer Foundation. H.G. is the recipient of a Susan Komen Cancer Foundation Career Development Award from the American Association for Cancer Research.

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Corresponding authors

Correspondence to Mohamed Bentires-Alj or Haihua Gu.

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Competing interests

Some of the information in this publication is related to the patent application US 10/424,570 “p97/Gab2 Gene, Genetically Manipulated Animals and Methods of Use Thereof” filed by The Beth Israel Deaconess Medical Center. B.G. Neel and H. Gu are listed as inventors on this application.

Supplementary information

Supplementary Fig. 1

Gab2 exprssion in retrovirally transduced MCF10A cells. (PDF 25 kb)

Supplementary Fig. 2

Gab2 promotes formation of multiacinar structures through Shp2. (PDF 210 kb)

Supplementary Fig. 3

Expression of Gab2 has no effect on activation of Stat5 in MCF10A cells in three-dimensional culture. (PDF 29 kb)

Supplementary Fig. 4

Expression of Gab2 has no effect on activation of Akt in MCF10A cells in three-dimensional culture. (PDF 32 kb)

Supplementary Fig. 5

Expression of wild-type and mutant Gab2 in MCF10A cells. (PDF 26 kb)

Supplementary Fig. 6

Whole mounts of mammary glands from MMTV-Gab2 transgenic mice. (PDF 70 kb)

Supplementary Fig. 7

Analysis of the phosphorylation status of Erk in normal mammary glands and mammary tumors from MMTV-NeuNT transgenic mice. (PDF 74 kb)

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Bentires-Alj, M., Gil, S., Chan, R. et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med 12, 114–121 (2006). https://doi.org/10.1038/nm1341

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