G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors with more than 1000 members yet only a select few GPCRs exhibit oncogenic activity. Among these, the protease-activated receptor 1 (PAR1) has been identified as an oncogene in the transformation of NIH3T3 fibroblasts. Moreover, expression of PAR1 is strongly correlated with invasive propensity across the NCI-60 cancer panel. We and others have shown that signaling from PAR1 plays a major role in the pathological invasion and metastatic processes of cancer cells from breast, melanoma, pancreatic and prostate tumors. This proposal will investigate the role of the protease-activated receptor PAR1 in the malignant progression of breast cancer. The preliminary data presented here strongly suggest that matrix metalloproteases secreted from stromal fibroblasts are directly cleaving and activating PAR1 on the surface of breast cancer cells.
Aim 1 will investigate the role of tumor and stromal-derived MMP1 versus thrombin in PAR 1-dependent cancer cell migration and invasion and determine whether MMP-PAR1 signaling constitutes a novel paracrine system of outward invasion. There is strong evidence that supports a bridging role for the recently described CCN gene family members cystein-rich 61 (Cyr61) in PAR1-dependent signaling through the activation of MMPs during angiogenesis and tissue remodeling.
In aim 2, we test the hypothesis that PAR1 activation may regulate cancer-stromal MMP production via Cyr61. The paracrine/autocrine role of PAR mediated Cyr61 regulation of MMP production may play a critical role in tumor invasion and angiogenesis and will be evaluated in in vitro systems. We recently established a new technology based on cell-penetrating peptides known as pepducins as a novel approach of inhibiting signaling between selected receptors and G proteins. Pepducins provide us with a unique, simple and fast way of testing the potential therapeutic value of blockade of a particular signaling pathway.
Aim 3 will use cell-penetrating pepducins to evaluate PARs as potential therapeutic targets in the treatment of breast cancer using both in vitro and mouse model systems.
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