The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway.
Recent evidence supports a role for EphB receptor tyrosine kinases as tumour suppressors in colorectal and prostate cancer. However, it is unclear how these receptors inhibit cancer cell tumorigenicity - an activity that is highly unusual for a family of receptor tyrosine kinases. Here, we report that the EphB4 receptor can behave as a tumour suppressor in a mouse xenograft model of breast cancer when stimulated by its ligand, ephrin-B2. In breast cancer cells, EphB4 activates an antioncogenic pathway involving Abl family tyrosine kinases and the Crk adaptor protein. This Abl-Crk pathway inhibits breast cancer cell viability and proliferation in addition to motility and invasion, and also downregulates the pro-invasive matrix metalloprotease, MMP-2. Consistent with these effects, EphB4 and the Abl-Crk pathway are constitutively active in non-transformed mammary epithelial cells. These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression.
Noren
Nicole K
NK
Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Foos
Gabriele
G
Hauser
Craig A
CA
Pasquale
Elena B
EB
D000818:Animals; D001549:Benzamides; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D036224:Receptor, EphB4 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D001549:Benzamides; D036388:Ephrin-B2; D007141:Immunoglobulin Fc Fragments; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; D036224:Receptor, EphB4; D016315:Proto-Oncogene Proteins c-abl; D020778:Matrix Metalloproteinase 2