A role for the scaffolding adapter GAB2 in breast cancer

Abstract

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.

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Acknowledgements

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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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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