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

Abstract

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.

• Authors: Nga Nguyen, Athan Kuliopulos, Roger A Graham, Lidija Covic
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 5 Pg. 2658-65 (Mar 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16510585 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCN1 protein, human
• Cysteine-Rich Protein 61
• Immediate-Early Proteins
• Intercellular Signaling Peptides and Proteins
• Matrix Metalloproteinase Inhibitors
• Receptor, PAR-1
• Matrix Metalloproteinase 1

Topics

• Animals
• Breast Neoplasms (enzymology, pathology)
• Cell Communication (genetics, physiology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Coculture Techniques
• Cysteine-Rich Protein 61
• Enzyme Induction
• Fibroblasts (enzymology, pathology)
• Gene Silencing
• Humans
• Immediate-Early Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics, physiology)
• Matrix Metalloproteinase 1 (biosynthesis, genetics, physiology)
• Matrix Metalloproteinase Inhibitors
• Mice
• NIH 3T3 Cells
• Receptor, PAR-1 (physiology)
• Stromal Cells (enzymology, pathology)