Yin and Yang of Heparanase in Breast Cancer Initiation
Abstract
Heparanase (HPR1) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a main constituent on the cell surface and in the extracellular matrix and basement membrane. Here we report that sulodexide, a HPR1 inhibitor, unexpectedly stimulates breast tumorigenesis and tumor growth of polyoma virus middle T antigen (PyMT)-induced breast tumor in a somatic breast cancer models. In contrast, HRP1 knockdown in a Neutransformed breast cancer cell line derived from TVA (the receptor for sub-group A avian leucosis virus)-transgenic mice led to a significant reduction of tumor growth in a syngeneic mouse model. Consistently, TVA-transgenic mice infected with a HPR1-miRNA construct delayed the Neu oncogene-induced breast cancer development. To determine whether the HPR1 activity was disposable for its stimulatory effect on breast cancer formation, the C-terminus of HPR1 gene, which lacks the HPR1 activity (designated as RCAS-8C), and a HPR1 enzymatically-inactive, dead HPR1 (designated as RCAS-dHPR1), were cloned into a RCAS vector and tested for their potency to stimulate breast cancer formation. In vitro studies revealed that both dHPR1 and HPR1 were capable of stimulating both PI-3 and MAP kinase pathway in three cell lines, including DF-1 fibroblast cell line, a RCAS-Neu murine breast cancer cell line, and a KAT-18 thyroid tumor cell line. Mice infected with RCAS-Neu virus plus RCAS-8C developed breast cancer more rapidly than that those infected with RCAS-Neu plus a control vector encoding green fluorescence protein. Similar observations were breast cancer in TVA-transgenic mice. Consistently, full-length, enzymatic active HPR1 also accelerated the formation of RCAS-Neu and RCAS-PyMT-induced breast cancer in TVA transgenic mice. Our results collectively suggest that the C-terimus of HPR1 is capable of promoting tumor growth, and its enzymatic activity is disposable for the tumor promoting activity of HPR1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2014
- Accession Number
- ADA613408
Entities
People
- Xiulong Xu
Organizations
- Rush University