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Cancer Res. 2006 Mar 1;66(5):2658-65.

Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells.

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Division of Hematology/Oncology, Molecular Oncology Research Institute, New England Medical Center, Boston, Massachusetts 02111, USA.


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.

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