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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)

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