Yin and Yang of Heparanase in Breast Cancer Initiation.

摘要

Heparanase-1 (HPR1) is an endoglycosidase overexpressed in many malignancies including breast cancer (1; 2). Previous studies suggest that the enzymatic activity of HPR1 can promote tumor angiogenesis and growth by degrading extra cellular matrix and releasing the growth factors. Since the C- terminus of HPR1 can activate the PI-3 kinase pathway and induce endothelial and tumor cell migration independent of its enzymatic activity, it is not clear whether its enzymatic activity or C-terminus or both contribute to breast tumor initiation and growth. The goal of this project is to dissect the opposing effect of HPR1 enzymatic activity and HPR1 C-terminus epitope on breast tumor initiation in a clinically relevant mouse breast cancer model. We proposed to determine if HPR1 knockdown will suppress or accelerate breast tumor initiation mediated by three oncogenes, PyMT, Neu and Wnt, and whether HPR1 C-terminus or an enzymatically dead HPR1 can stimulates breast tumor initiation, whereas full- length HPR1 has no effect or is less effective in stimulating breast tumor initiation and progression.