This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nguyen, N. Articles by Covic, L. Search for Related Content PubMed PubMed Citation Articles by Nguyen, N. Articles by Covic, L.

Tumor-Derived Cyr61(CCN1) Promotes Stromal Matrix Metalloproteinase-1 Production and Protease-Activated Receptor 1–Dependent Migration of Breast Cancer Cells

Division of Hematology/Oncology, Molecular Oncology Research Institute, New England Medical Center and Departments of Medicine, Tufts University School of Medicine, Boston, Massachusetts

Requests for reprints: Lidija Covic, Division of Hematology/Oncology, Molecular Oncology Research Institute, New England Medical Center, Box 7510, 75 Kneeland Street, Boston, MA 02111. Fax: 617-636-7855; E-mail: lcovic{at}tufts-nemc.org.

Matrix metalloproteinases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. Here, we show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells toward the fibroblasts. Cyr61-dependent loss of migration was complemented by exogenous MMP-1 and required the presence of the functional PAR1 receptor on the breast cancer cells. These results suggest that interrupting tumor-stromal cell communication by targeting Cyr61 may provide an alternative therapeutic approach for the treatment of invasive breast cancer. (Cancer Res 2006; 66(5): 2658-65)

This article has been cited by other articles:

				A. S. Dobroff, H. Wang, V. O. Melnikova, G. J. Villares, M. Zigler, L. Huang, and M. Bar-Eli Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma J. Biol. Chem., September 18, 2009; 284(38): 26194 - 26206. [Abstract] [Full Text] [PDF]

				E. Yang, A. Boire, A. Agarwal, N. Nguyen, K. O'Callaghan, P. Tu, A. Kuliopulos, and L. Covic Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis Cancer Res., August 1, 2009; 69(15): 6223 - 6231. [Abstract] [Full Text] [PDF]

				T. J. Wilson, K. C. Nannuru, and R. K. Singh Cathepsin G Recruits Osteoclast Precursors via Proteolytic Activation of Protease-Activated Receptor-1 Cancer Res., April 1, 2009; 69(7): 3188 - 3195. [Abstract] [Full Text] [PDF]

				C. T. Walsh, J. Radeff-Huang, R. Matteo, A. Hsiao, S. Subramaniam, D. Stupack, and J. H. Brown Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61 FASEB J, November 1, 2008; 22(11): 4011 - 4021. [Abstract] [Full Text] [PDF]

				R. Meyuhas, E. Pikarsky, E. Tavor, A. Klar, R. Abramovitch, J. Hochman, T. G. Lago, and A. Honigman A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells Mol. Cancer Res., September 1, 2008; 6(9): 1397 - 1409. [Abstract] [Full Text] [PDF]

				A. Agarwal, L. Covic, L. M. Sevigny, N. C. Kaneider, K. Lazarides, G. Azabdaftari, S. Sharifi, and A. Kuliopulos Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer Mol. Cancer Ther., September 1, 2008; 7(9): 2746 - 2757. [Abstract] [Full Text] [PDF]

				C. T. Walsh, D. Stupack, and J. H. Brown G Protein-Coupled Receptors Go Extracellular: RhoA Integrates the Integrins Mol. Interv., August 1, 2008; 8(4): 165 - 173. [Abstract] [Full Text] [PDF]

				M.-T. Lin, I-H. Kuo, C.-C. Chang, C.-Y. Chu, H.-Y. Chen, B.-R. Lin, M. Sureshbabu, H.-J. Shih, and M.-L. Kuo Involvement of Hypoxia-inducing Factor-1{alpha}-dependent Plasminogen Activator Inhibitor-1 Up-regulation in Cyr61/CCN1-induced Gastric Cancer Cell Invasion J. Biol. Chem., June 6, 2008; 283(23): 15807 - 15815. [Abstract] [Full Text] [PDF]

				M. Hatziapostolou, C. Polytarchou, D. Panutsopulos, L. Covic, and P. N. Tsichlis Proteinase-Activated Receptor-1-Triggered Activation of Tumor Progression Locus-2 Promotes Actin Cytoskeleton Reorganization and Cell Migration Cancer Res., March 15, 2008; 68(6): 1851 - 1861. [Abstract] [Full Text] [PDF]

				R. S. O'Connor, S. T. Mills, K. A. Jones, S. N. Ho, and G. K. Pavlath A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis J. Cell Sci., January 1, 2007; 120(1): 149 - 159. [Abstract] [Full Text] [PDF]