Involvement of Heparanase in Breast Carcinoma Progression
Abstract
Primary tumors produced by MCF-7 breast carcinoma cells over-expressing the mostly intracellular human enzyme, exhibited a 3-4 fold accelerated growth compared with tumors produced by mock-transfected cells. A more pronounced increase in tumor size and vascularity was observed with MCF-7 cells over-expressing a secreted form of heparanase, indicating that cellular localization of heparanase plays an important role in breast tumor progression. Translocation, secretion and processing of heparanase were stimulated in response to estrogen. Estrogen also stimulated heparanase promoter activity and gene expression in MCF-7 cells. This effect was abolished by the pure antiestrogen ICI 182,780, but not tamoxifen. Our data suggest a mechanism through which estrogen, independent of its proliferative effect, may induce heparanase overexpression and thereby promote tumor-stromal interactions, critical for breast carcinoma progression. The involvement of heparanase in morphogenesis and neoplastic alterations was demonstrated in transgenic mice over-expressing the heparanase enzyme. Mammary glands of these mice exhibited precocious branching and widening of ducts, as well as early signs of hyperplasia and basement membrane disruption. Progress was made in characterization and purification of a proteolytic activity expressed by MDA-435 breast carcinoma cells and involved in processing and activation of latent heparanase. Our results indicate that heterodimer formation between the 8 kDa and 50 kDa heparanase subunits is necessary for heparanase enzymatic activity. Heparanase offers an attractive drug target. Lead heparanase-inhibiting species of laminaran sulfate and chemically modified glycol-split derivatives of heparin were prepared, characterized and found to efficiently inhibit experimental metastasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA418151
Entities
People
- Israel Vlodavsky
- Tamar Peretz
- Yael Friedmann