PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.
Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biology. PAR1 is proposed to be involved in the invasive and metastatic processes of various cancers. However, the protease responsible for activating the proinvasive functions of PAR1 remains to be identified. Here, we show that expression of PAR1 is both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft model. Further, we show that the matrix metalloprotease, MMP-1, functions as a protease agonist of PAR1 cleaving the receptor at the proper site to generate PAR1-dependent Ca2+ signals and migration. MMP-1 activity is derived from fibroblasts and is absent from the breast cancer cells. These results demonstrate that MMP-1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.
Boire
Adrienne
A
Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.
Covic
Lidija
L
Agarwal
Anika
A
Jacques
Suzanne
S
Sherifi
Sheida
S
Kuliopulos
Athan
A
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D020013:Calcium Signaling / Q000502:physiology; D002277:Carcinoma / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D044463:Receptor, PAR-1 / Q000378:metabolism*; D014183:Transplantation, Heterologous
D044463:Receptor, PAR-1; D020781:Matrix Metalloproteinase 1