Poster Presentation 29th Lorne Cancer Conference 2017

Investigating the role of heparanase in breast cancer progression using the PyMT-MMTV mouse model (#180)

Krish Jayatilleke 1 , Alyce Forrest 1 , Shaun Gaskin 1 , Belinda Parker 1 , Mark Hulett 1
  1. La Trobe Institute for molecular science, La Trobe University, Bundoora, VIC, Australia

Breast cancer is the second most common cancer in Australian women. The enzymatic activity of heparanase expressed by breast carcinoma cells has been implicated in the ability of tumour cells to metastasise. 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 the 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 pro-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 generated a heparanase-deficient mouse line (HPSE-/- C57BL/6) and novel heparanase inhibitors for defining the role and importance of heparanase in tumour progression. It is shown that the tumour stroma positively contributes to intra-tumoural heparanase activity, which may further enhance tumour growth. The role of heparanase in tumour immunosurveillance is also investigated. In order to define the role of heparanase in the progression of breast cancer, PyMT-MMTV transgenic mice crossed with constitutive HPSE-/- mice are utilised.