Protease Activated Receptors (PARs) in th Malignant Invasion Process
Abstract
Protease Activated Receptors (PARs) are G-protein - coupled receptors consisting of four family members, all which are activated via proteolytic cleavage. Our data stems from prior observations indicating that thrombin receptor, PAR1 plays a central role in breast carcinoma invasion and metastasis, The mammary gland provides a powerful tool to study developmental and pathological (breast tumor progression) aspects of the gland. We prepared now mice carrying an MMTV LTR - driven Par-1 transgenes specifically overexpressed in the mammary glands. Analysis of whole mount glands of virgin hPar1 +1- mice, showed enhanced complexity of alveolar side branching as compared with normal virgin glands. A striking ductal side branching, budding from preexisting ducts was observed in hPar1 overexpressing glands of pregnant mice. This phenotype is precociously reminiscent of the effect of several oncogenes in the mouse breast. Syk, a tandem SH2 tyrosine kinase protein widely expressed in hematopoeitic cells has been recently assigned as a potent tumor suppressor gene in human breast carcinoma. We set-out to analyze the interrelation between the breast invasive phenotype and Syk, more specifically, the mutual interactions between hParl and Syk. The recruitment of new blood vessels is a prerequisite for tumor growth and metastasis. While recently it has been shown that PAR1 plays a critical role in endothelial cell embryonic development rescuing Par 1 -/- mice from bleeding to death - its role in tumor angiogenesis is unknown. We have addressed this issue by applying the Matrigel plug assay and investigated whether hPar1 can elicit tumor angiogenesis in vivo. Our approach involving the combined analyses of tissue specific hPar1 transgenes, biopsy specimens and established cell lines may help elucidate the involvement of PAR1 in tumor metastasis and angiogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2002
- Accession Number
- ADA407557
Entities
People
- Beatrice Uziely
- Rachel Sar-shavit
Organizations
- Hadassah Medical Center