How Is EphB4 Abl to Suppress Tumors?

Abstract

Although receptor tyrosine kinases are often linked to tumor growth, members of the Eph family appear to function as tumor suppressors. Noting that EphB4 has been found in breast cancer cells and that its mRNA has been identified in breast cancer cell lines, Noren et al. confirmed that EphB4 was present in various breast cancer cell lines. The ligand ephrin-B2, however, was absent or present in low abundance in breast cancer lines, although it was abundant in MCF-10A cells, a nontransformed breast epithelial line. Consistent with this, EphB4 was highly phosphorylated in MCF-10A cells but not in MDA-MB-435 human breast cancer cells. Intraperitoneal administration of a chimeric protein containing the dimerized extracellular domain of ephrin-B2 (ephrin-B2 Fc) slowed tumor growth in mice bearing tumors derived from a clonal line of MDA-MB-435 cells (MDA-MB-435c). Ephrin-B2 Fc elicited tyrosine phosphorylation of the adaptor protein Crk, a target of Abl family nonreceptor tyrosine kinases, in MDA-MB-435c cells. Moreover, experiments with the Abl kinase inhibitor Gleevec, a Gleevec-insensitive Abl mutant, and siRNA indicated that Crk phosphorylation depended on the Abl family kinases Abl and Arg. Ephrin-B2 Fc inhibited the proliferation and survival of MDA-MB-435c cells grown in spheroids and also inhibited breast cancer cell migration toward fibronectin and expression of the MMP-2 matrix metalloprotease. These effects were mediated by the Abl-Crk pathway and blocked by Gleevec, which also blocked inhibition of tumor growth by ephrin-B2 Fc in the mouse xenograft model. Thus, the authors conclude that EphB4 may be an appropriate target for breast cancer therapy. Wang discusses the results in the context of Gleevec's use in cancer therapy. N. K. Noren, G. Foos, C. A. Hauser, E. B. Pasquale, The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat. Cell Biol. 8 , 815-825 (2006). [PubMed] J. Y. Wang, Eph tumour suppression: The dark side of Gleevec. Nat. Cell Biol. 8 , 785-786 (2006). [PubMed]