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The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway

Nature Cell Biology volume 8, pages 815–825 (2006)Cite this article

An Erratum to this article was published on 01 September 2006

Abstract

Recent evidence supports a role for EphB receptor tyrosine kinases as tumour suppressors in colorectal and prostate cancer. However, it is unclear how these receptors inhibit cancer cell tumorigenicity — an activity that is highly unusual for a family of receptor tyrosine kinases. Here, we report that the EphB4 receptor can behave as a tumour suppressor in a mouse xenograft model of breast cancer when stimulated by its ligand, ephrin-B2. In breast cancer cells, EphB4 activates an antioncogenic pathway involving Abl family tyrosine kinases and the Crk adaptor protein. This Abl–Crk pathway inhibits breast cancer cell viability and proliferation in addition to motility and invasion, and also downregulates the pro-invasive matrix metalloprotease, MMP-2. Consistent with these effects, EphB4 and the Abl–Crk pathway are constitutively active in non-transformed mammary epithelial cells. These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression.

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Figure 1: Ephrin-B2 Fc treatment inhibits tumour growth in a xenograft model.
Figure 2: Treatment of breast cancer cells with ephrin-B2 Fc enhances Crk tyrosine phosphorylation.
Figure 3: Treatment of breast cancer cells with ephrin-B2 Fc increases Crk phosphorylation on Tyr 221 in an Abl-dependent manner.
Figure 4: Inhibition of cell proliferation and survival by ephrin-B2 Fc requires Abl kinase activity and Crk adaptor function.
Figure 5: Treatment with ephrin-B2 Fc inhibits breast cancer cell migration and invasion and MMP-2 expression.
Figure 6: Inhibition of cell migration and MMP-2 expression by ephrin-B2 Fc requires Abl kinase activity and Crk adaptor function.
Figure 7: Inhibition of spheroid and tumour growth by ephrin-B2 Fc requires Abl kinase activity.
Figure 8: Inhibition of endogenous ephrin-B2 binding to EphB4 in non-transformed mammary epithelial cells.

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Acknowledgements

We thank J. Y. J. Wang for the Abl constructs, including the Gleevec-insensitive mutant AblTI, Novartis for the Gleevec, K. Vuori for the Crk constructs, D.T. Scaddon for pcDNA3–EphB4, the high throughput cell analysis facility of The Burnham Institute, D. Rozanov and A. Howes for technical advice and C. Bourgin and E. Ruoslahti for comments on the manuscript. This work was supported by University of California Breast Cancer Program Grants (E.B.P.), National Institute of Health Grants (E.B.P.) and a Department of Defense postdoctoral fellowship (N.K.N).

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  1. Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, 92037, CA, USA

    Nicole K. Noren, Gabriele Foos, Craig A. Hauser & Elena B. Pasquale

  2. Pathology Department, University of California San Diego, La Jolla, 92093, CA, USA

    Elena B. Pasquale

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G.F. and C.A.H. contributed the MDA-MB-435c clonal cell line and helpful disscussions. N.K.N. performed the experiments and N.K.N. and E.B.P. designed the project and performed the data analysis.

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Correspondence to Elena B. Pasquale.

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Noren, N., Foos, G., Hauser, C. et al. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway. Nat Cell Biol 8, 815–825 (2006). https://doi.org/10.1038/ncb1438

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