Protease Activated Receptors in the Malignant Invasion Process
Abstract
Protease-Activated Receptors (PARs) are G-coupled seven transmembrane domain proteins consisting of 4 family members and activated via proteolytic cleavage. In addition to their traditional role in hemostasis, thrombosis and vascular biology, PAR1, thrombin receptor, the first prototype of the family emerges with surprisingly novel functions in tumor biology. We have assigned a central role for PAR1 in breast carcinoma invasion, metastasis and angiogenesis. The notion that hPar1 is one of a series of genes that are part of an invasive program stems from our studies showing that hPar1 is exclusively expressed along the time limited placenta physiological invasion process to the uterus decidua during implantation, completely shuts off thereafter. The use of breast carcinoma clones overexposing different forms of hPar1 (e.g., lull length, a truncated version and antisense hPar1) as also tetracycline inducible hPar1! system have enabled the elucidation of a specific "invadopodia" signaling pathway and the relative contribution of hPar1 during breast carcinoma progression and angiogenesis. In parallel, we have established an original line of mice over-expressing MMTV LTR - driven hpar-1 targeted to the mammary glands. The glands exhibited grossly hyperplastic features as compared with the non transgenic littermates. This phenotype is precociously reminiscent of the effect of several oncogene overexpression in the mouse breast. We propose now a novel pathway of wnt activation as a consequence of hPar1 overexpression in the mammary glands. Our approach involving the combined analyses of tissue specific hPar1 transgenes, biopsy specimens and established cell lines are combined to assist evaluating the involvement of hPar1 in breast carcinoma invasion, metastasis and angiogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA418137
Entities
People
- Beatrice Vziely
- Rachel Bar-shavit