Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells.
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.
Nguyen
Nga
N
Division of Hematology/Oncology, Molecular Oncology Research Institute, New England Medical Center, Boston, Massachusetts 02111, USA.
Kuliopulos
Athan
A
Graham
Roger A
RA
Covic
Lidija
L
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D018920:Coculture Techniques; D055515:Cysteine-Rich Protein 61; D004790:Enzyme Induction; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D041681:NIH 3T3 Cells; D044463:Receptor, PAR-1 / Q000502:physiology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D044463:Receptor, PAR-1; D020781:Matrix Metalloproteinase 1