Role of Notch/VEGF-Receptor 3 in Breast Tumor Angiogenesis and Lymphangiogenesis

摘要

The overall objective is to define the interaction between Notch and VEGFR-3 signaling in breast cancer. We are examining a role for Notch in breast tumor vessels and attempting to block Notch and VEGFR-3 activity in breast tumors grown in mice. We proposed two aims: 1) studies of Notch/Dll4 function in murine mammary tumorigenesis and 2) studies of the inhibitory effects of a Notch antagonist (Notch decoy) in a murine mammary tumor model. In aim 1, to study the role for notch in murine mammary tumorigenesis, progress has been made in developing two new transgenic lines that will allow for conditional activation or inactivation of Notch specifically within the endothelium. The first mouse line, EFi-Notchi IC can be manipulated in a conditional fashion, as demonstrated by lethality if activated in embryonic endothelium. The second mouse line, EFl-NotchlECDIFc, has been generated and is being further tested. We have carried out experiments to demonstrate that breast tumor xenograft growth is inhibited by the Notch decoy, an antagonist made up of the Notchi extracellular domain fused to the Fc protein, Notch1 ECDIFc. This block appears to be a result of reduced tumor angiogenesis. This strategy, now shown to inhibit mammary tumor growth in our mouse models, is proving to be a promising area for therapeutic intervention in breast cancer.