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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104406-05
Application #
7638429
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2005-09-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$305,243
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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Austin, Karyn M; Covic, Lidija; Kuliopulos, Athan (2013) Matrix metalloproteases and PAR1 activation. Blood 121:431-9
Michael, E S; Kuliopulos, A; Covic, L et al. (2013) Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis. Am J Physiol Gastrointest Liver Physiol 304:G516-26
O'Callaghan, Katie; Lee, Lydia; Nguyen, Nga et al. (2012) Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. Blood 119:1717-25
O'Callaghan, Katie; Kuliopulos, Athan; Covic, Lidija (2012) Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J Biol Chem 287:12787-96
Foley, Caitlin J; Luo, Chi; O'Callaghan, Katie et al. (2012) Matrix metalloprotease-1a promotes tumorigenesis and metastasis. J Biol Chem 287:24330-8
Tressel, Sarah L; Kaneider, Nicole C; Kasuda, Shogo et al. (2011) A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol Med 3:370-84
Tressel, Sarah L; Koukos, Georgios; Tchernychev, Boris et al. (2011) Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol Biol 683:259-75
Sevigny, Leila M; Zhang, Ping; Bohm, Andrew et al. (2011) Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc Natl Acad Sci U S A 108:8491-6
Agarwal, Anika; Tressel, Sarah L; Kaimal, Rajani et al. (2010) Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy. Cancer Res 70:5880-90

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