This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kumar, S. R. Articles by Gill, P. S. Search for Related Content PubMed PubMed Citation Articles by Kumar, S. R. Articles by Gill, P. S.

(American Journal of Pathology. 2006;169:279-293.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050889

Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast Cancer

S. Ram Kumar^*, Jasbir Singh, Guangbin Xia, Valery Krasnoperov, Loubna Hassanieh, Eric J. Ley^¶, Jeffrey Scehnet^*, Neil G. Kumar, Debra Hawes^*, Michael F. Press^*, Fred A. Weaver and Parkash S. Gill^*

From the Departments of Pathology,^* Surgery, Medicine, and Colorectal Surgery,^¶ Keck School of Medicine, University of Southern California, Los Angeles, and VasGene Inc., Los Angeles, California

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 ODN-treated 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.

This article has been cited by other articles:

				H. L. Holen, M. Shadidi, K. Narvhus, O. Kjosnes, A. Tierens, and H.-C. Aasheim Signaling through ephrin-A ligand leads to activation of Src-family kinases, Akt phosphorylation, and inhibition of antigen receptor-induced apoptosis J. Leukoc. Biol., October 1, 2008; 84(4): 1183 - 1191. [Abstract] [Full Text] [PDF]

				E. J. Yavrouian, U. K. Sinha, D. H. Rice, M. T. Salam, P. S. Gill, and R. Masood The Significance of EphB4 and EphrinB2 Expression and Survival in Head and Neck Squamous Cell Carcinoma Arch Otolaryngol Head Neck Surg, September 1, 2008; 134(9): 985 - 991. [Abstract] [Full Text] [PDF]

				N. K. Noren and E. B. Pasquale Paradoxes of the EphB4 Receptor in Cancer Cancer Res., May 1, 2007; 67(9): 3994 - 3997. [Abstract] [Full Text] [PDF]

				V. Davalos, H. Dopeso, J. Castano, A. J. Wilson, F. Vilardell, J. Romero-Gimenez, E. Espin, M. Armengol, G. Capella, J. M. Mariadason, et al. EPHB4 and Survival of Colorectal Cancer Patients. Cancer Res., September 15, 2006; 66(18): 8943 - 8948. [Abstract] [Full Text] [PDF]