Pepducin Based Intervention of Breast Cancer Invasion
Final rept. 15 Jul 2005-14 Jul 2006
TUFTS-NEW ENGLAND MEDICAL CENTER BOSTON MA
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Matrix metalloproteases 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 Cyr61CCN1 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 inmigration of the cancer cells towards the fibroblasts. Cyr61-dependent loss of migration was complemented byexogenous 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.
- Medicine and Medical Research