Involvement of Heparanase in Breast Carcinoma Progression
Annual rept. 1 Jun 2000-31 May 2001
HADASSAH MEDICAL ORGANIZATION JERUSALEM (ISRAEL)
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Observations obtained during the first year of research focusing on the three main tasks of the original application support the proposed involvement of heparanase heparan sulfate degrading endoglycosidase in breast carcinoma progression. A straight forward indication is the accelerated growth of tumors produced by MCF-7 cells over-expressing the heparanase gene and enzyme, versus tumors produced by control mock-transfected MCF-7 breast cancer cells. Mammary glands of transgenic mice over-expressing the heparanase enzyme exhibited precocious branching of ducts and early signs of hyperplasia and basement membrane disruption. We have cloned the heparanase promoter region flied to a luciferase reporter gene and demonstrated a significant stimulation by estrogen of both heparanase promoter activity and gene expression. Deletion experiments identified regions in the heparanase promoter necessary for its activity in transfected MDA-435 cells. Experimental approaches for achieving the other objectives of the proposed research were developed. Among these is a system to purify and characterize a proteolytic activity secreted by highly metastatic breast carcinoma cells, involved in processing and activation of the 65 kDa latent heparanase. Potent heparanase-inhibiting fragments derived from laminaran sulfate were prepared. The biochemical nature of these oligosaceharids and their efficacy in experimental models of breast carcinoma are being evaluated.
- Medicine and Medical Research