Receptor tyrosine kinases of the Eph family are upregulated in different types of cancer. EphB4 has been linked to breast cancer and other types of cancer, but little is known about how this receptor may contribute to oncogenesis. The EphB receptors transmit signals via their kinase domain (known as forward signals) and also through the cytoplasmic domain of their transmembrane ephrin-B ligands (known as reverse signals). We found that EphB4 promotes breast cancer cell growth in vivo by stimulating angiogenesis through its ligand, ephrin-B2, which is expressed in tumor blood vessels. This is consistent with the well-established role of EphB4 and ephrin-B2 in blood vessel formation during embryonic development and with the emerging role of these molecules in pathological forms of angiogenesis. Surprisingly, we found that EphB4 forward signaling activity is low in breast cancer cells because of the low levels of ephrin-B2. Furthermore, in vitro stimulation of EphB4 with an ephrin-B2 Fc fusion protein inhibits breast cancer cell survival/proliferation and migration/invasion, suggesting that EphB4 forward signaling inhibits tumorigenesis. These findings are in agreement with a recent report that EphB receptor activity suppresses colorectal cancer progression (Batlle et al., 2005, Nature 435:1126). We have identified a novel Eph signaling pathway responsible for the tumor suppressing effects of EphB4 that involves the cytoplasmic tyrosine kinase Abl and the proto-oncogene Crk. Activation of this pathway by systemic administration of ephrin-B2 Fc inhibits tumor growth in a mouse breast cancer xenograft model. Despite this progress, much remains to be learned about how EphB4 and ephrin-B2 influence tumor progression. Here we propose to use a combination of in vitro cell culture assays and in vivo mouse tumor models to better understand the tumor suppressing and tumor promoting activities of EphB4/ephrin-B2, in order to optimally exploit EphB4 as a breast cancer target. Furthermore, we will develop peptides and small molecules that target EphB4 and evaluate their anti-oncogenic effects in cell culture and in mouse preclinical models. The EphB4-targeting molecules that we propose to develop will also be useful for therapies against vascular diseases involving EphB4 and ephrin-B2. The information obtained will advance our basic understanding of the complex but intriguing molecular mechanisms used by the Eph receptors to influence tumorigenesis and angiogenesis, and possibly lead to new Eph-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116099-04
Application #
7651424
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$387,328
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Duggineni, Srinivas; Mitra, Sayantan; Noberini, Roberta et al. (2013) Design, synthesis and characterization of novel small molecular inhibitors of ephrin-B2 binding to EphB4. Biochem Pharmacol 85:507-13
Lisabeth, Erika M; Falivelli, Giulia; Pasquale, Elena B (2013) Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol 5:
Noberini, Roberta; Koolpe, Mitchell; Lamberto, Ilaria et al. (2012) Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res 66:363-73
Noberini, Roberta; Lamberto, Ilaria; Pasquale, Elena B (2012) Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol 23:51-7
Mace, Peter D; Wallez, Yann; Dobaczewska, Ma?gorzata K et al. (2011) NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling. Nat Struct Mol Biol 18:1381-7
Noberini, Roberta; Mitra, Sayantan; Salvucci, Ombretta et al. (2011) PEGylation potentiates the effectiveness of an antagonistic peptide that targets the EphB4 receptor with nanomolar affinity. PLoS One 6:e28611
Prigozhina, Natalie L; Heisel, Andrew; Wei, Ke et al. (2011) Characterization of a novel angiogenic model based on stable, fluorescently labelled endothelial cell lines amenable to scale-up for high content screening. Biol Cell 103:467-81
Yang, Nai-Ying; Lopez-Bergami, Pablo; Goydos, James S et al. (2010) The EphB4 receptor promotes the growth of melanoma cells expressing the ephrin-B2 ligand. Pigment Cell Melanoma Res 23:684-7
Murai, Keith K; Pasquale, Elena B (2010) Restraining stem cell niche plasticity: a new talent of Eph receptors. Cell Stem Cell 7:647-8

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