Pleiotrophin Signaling Through PTNR in Breast Cancer
Annual summary rept. 1 Apr 2000-31 Mar 2001
GEORGETOWN UNIV WASHINGTON DC MEDICAL CENTER
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Angiogenesis, the formation of new blood vessels from pre-existing ones, plays an important role in breast cancer growth and metastasis. The rational design of novel drugs targeting angiogenesis requires an understanding of the signaling pathways that mediate angiogenesis, from growth factors through their receptors to the activation of intracellular signaling cascades. The pleiotrophin signaling pathway is known to be important in angiogenesis and breast cancer growth, but the exact mechanisms of pleiotrophin signaling remain undefined. We have recently identified a novel cell-surface receptor PTNR capable of mediating pleiotrophins mitogenic and angiogenic activities. Here we demonstrate the biologic relevance of pleiotrophin signaling through PTNR. By targeting PTNR in appropriate cell lines through the use of hammerhead ribozymes, we can reduce the endogenous levels of PTNR mRNA as demonstrated by a PTNR-specific RNase protection assay. In addition, signaling through PTNR can also be disrupted by overexpressing dominant-negative PTNR constructs in appropriate cell lines. The phenotype resulting from these two independent approaches can be demonstrated by analysis of the ability of altered tumor cells to form colonies in soft agar. A final goal is to determine the molecular interaction between pleiotrophin and PTNR by mutational analysis of the ligand-binding domain of PTNR.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology