Pepducin Based Intervention of Breast Cancer Invasion
Abstract
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 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 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2006
- Accession Number
- ADA458458
Entities
People
- Athan Kuliopulos
- Lidija Covic
- Nga Nguyen
- Roger A. Graham
Organizations
- Tufts Medical Center