Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast Cancer

Abstract

EphB4, a member of the largest family of receptor tyrosine kinases, is normally expressed on endothelial and neuronal cells. Although aberrant expression of EphB4 has been reported in several human tumors, including breast cancer, its functional significance is not understood. We report here that EphB4 is expressed in 7 of 12 (58%) human breast cancer specimens and 4 of 4 (100%) breast tumor cell lines examined. Overexpression of EphB4 in breast cancer cells was driven by gene amplification and by the erbB family of receptors via activation of Janus tyrosine kinase-signal transducers and activators of transcription and protein kinase B. The aberrantly expressed receptor was phosphorylated by its natural ligand, EphrinB2, and signaled via the protein kinase B pathway. Targeted knockdown of EphB4 expression by small interference RNA (and antisense oligodeoxynucleotides (ODNs)) led to dose-dependent reduction in cell survival, increased apoptosis, and sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Antisense ODN-mediated EphB4 knockdown resulted in reduced tumor growth in a murine tumor xenograft model. Antisense ODNtreated tumors were 72% smaller than control tumors at 6 weeks, with an 86% reduction in proliferating cells, 15-fold increase in apoptosis, and 44% reduction in tumor microvasculature. Our data indicate that biologically active EphB4 functions as a survival factor in breast cancer and is a novel target for therapy. (Am J

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…When ligand-induced receptor activation was restored with recombinant ephrin-B2, there was a significant decrease in cell survival. 84,85 Cumulatively, these results suggest that gain of ligand independent EphB4 signaling combined with loss of ephrin-B2 reverse signaling facilitates breast cancer progression.…”

“…Additionally, EphB4 was shown to be a key regulator of oncogenic phenotypes in breast cancer cells since its loss or inhibition reduced survival, anti-apoptotic proteins, migration, invasion, tumor size, and vascularity. 84,85 In the breast carcinoma cell lines tested, robust expression of EphB4 correlated with little to no detection of its cognate ligand, ephrin-B2. When ligand-induced receptor activation was restored with recombinant ephrin-B2, there was a significant decrease in cell survival.…”

The role of FoxC1 in early Xenopus development

“…In several contexts, Ephs have been implicated in cell survival and prevention of apoptosis (Yue et al, 1999;Dohn et al, 2001;Depaepe et al, 2005;Freywald et al, 2006;Kumar et al, 2006). Also, loss of adhesion in early Xenopus embryos, occurring with major alterations in gene expression, is often accompanied by apoptosis (Sible et al, 1997).…”

The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome

“…The Eph receptors are the largest family of tyrosine kinases, comprising of 15 individual members, divided into EphA and EphB classes. Recently, several studies have documented high expression of the Eph family of receptor tyrosine kinases in tumours (Stephenson et al, 2001;Berclaz et al, 2003;Wu et al, 2004Wu et al, , 2006Lee et al, 2005;Xia et al, 2005Xia et al, , 2006Kumar et al, 2006;Masood et al, 2006). Although there is limited data on the protein levels of EphB4 in cancers, only recently, data on the biological significance of this protein in tumour biology is being accrued.…”