Breast cancer is the second most common cancer in Australian women. The enzymatic activity of heparanase expressed by breast carcinoma cells results in an elevated metastatic capability. Heparanase is a beta-D-endoglucuronidase that cleaves heparan sulphate (HS), an important structural component of the extracellular matrix (ECM) and vascular basement membrane (BM). The cleavage of HS by heparanase expressing cells such as metastatic tumour cells, proliferating endothelial cells, and activated leukocytes, has been proposed to facilitate degradation of the ECM/BM to promote cell invasion associated with tumour metastasis, angiogenesis and inflammation. HS chains in the ECM also bind an array of growth factors and cytokines, and the release of these by heparanase has been suggested to mediate angiogenic responses required for tumour growth. Heparanase therefore represents a highly promising drug target for the generation of new anti-metastatic, anti-angiogenic and anti-inflammatory therapies. Although heparanase has been strongly implicated for over two decades in tumour growth and metastasis, the precise function and contribution of the enzyme in the tumour microenvironment remain poorly defined. The Hulett laboratory has recently generated a heparanase-deficient mouse strain (C57BL/6 HPSE-/-) to define the role and importance of heparanase in tumour progression. This project utilises spontaneous mammary tumour developing PyMT-MMTV transgenic mice crossed with constitutive HPSE-/- mice. The resulting PyMT-MMTVx HPSE-/- mouse strain provides an ideal model to define the role of heparanase in the tumour microenvironment, especially in the early stages of breast carcinoma development. Furthermore, by the orthotopic implantation of wild type and HPSE-/- mouse mammary carcinoma cells into female mice followed by the subsequent surgical resection of tumours, the influence of heparanase in the microenvironment on metastatic progression of breast cancer will be determined.