Eph receptors in breast cancer: roles in tumor promotion and tumor suppression

David Vaught,Jin Chen,Dana M Brantley-Sieders

doi:10.1186/bcr2207

Abstract

Eph receptor tyrosine kinase signaling regulates cancer initiation and metastatic progression through multiple mechanisms. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. In addition, Eph molecules function in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of these molecules to promote carcinoma progression and metastasis. The complex nature of Eph receptor signaling and crosstalk with other receptor tyrosine kinases presents a unique challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer.

Highlights

The Eph receptors comprise the largest family of receptor tyrosine kinases
Implantation of tumor cells into the mammary gland of EphA2-deficient host mice results in reduced tumor volume, microvascular density, and lung metastasis. These findings suggest that loss of EphA2 in the tumor microenvironment impairs tumor angiogenesis and metastatic progression [24,45]
The available evidence suggests that ligand-induced Eph receptor signaling in tumor cells plays a role in tumor suppression, whereas ligand-independent Eph receptor signaling functions in tumor promotion

Summary

Introduction

The Eph receptors comprise the largest family of receptor tyrosine kinases. The family is subdivided into class A and class B, based on sequence homology and binding affinity for two distinct types of membrane-anchored ephrin ligands. EphA2-null endothelial cells reconstituted with EphA2 mutants lacking these binding sites fail to activate Rac GTPase, are defective in cell migration and assembly in vitro, and are unable to incorporate into tumor vasculature in vivo These findings suggest a critical role for these tyrosine phosphorylation sites in transducing EphA2 forward signaling in vascular endothelial cells and validated the involvement of PI3K-dependent activation of Vav exchange factors and Rac GTPase in ephrin-A1-induced angiogenesis. Proliferation of ephrin-B1 over-expressing cells was not affected in culture, soluble ephrin-B1-Fc enhanced endothelial cell proliferation and migration in vitro, suggesting that at least one function of ephrin-B1 in tumor progression involves facilitation of tumor angiogenesis [55,56] Taken together, these studies reveal a critical role for B class receptors and ligands in tumor progression and vascular recruitment for multiple types of human cancer. These preliminary results demonstrate that EphA2-derived epitopes may represent important candidate vaccines to be tested in clinical trials for the treatment of malignant cancers

Conclusions

Findings

Pasquale EB: Developmental cell biology