Poster Presentation 30th Lorne Cancer Conference 2018

Investigating the role of heparanase in breast cancer progression using the PyMT-MMTV mouse model (#175)

Krish Jayatilleke 1 , Hendrika Duivenvoorden 1 , Belinda Parker 1 , Mark Hulett 1
  1. La Trobe Institute for Molecular Science, Bundoora, VIC, Australia

Breast cancer is the second most common cancer in Australian women. Heparanase (HPSE) is a beta-D-endoglucuronidase that cleaves heparan sulphate (HS), an important structural component of the extracellular matrix (ECM) and the vascular basement membrane (BM). The cleavage of HS by HPSE expressing cells such as tumour cells and activated leukocytes degrades the ECM/BM to promote cell invasion associated with metastasis, angiogenesis and inflammation. HS chains in the ECM also bind growth factors and cytokines and the release of these by HPSE promotes tumour growth. However, the precise roles of HPSE in breast cancer as well as in the tumour microenvironment remain poorly defined. The Hulett laboratory has recently generated a HPSE-deficient C57Bl/6 mouse strain (C57Bl/6xHPSE-/-). These were crossed with spontaneous mammary tumour developing PyMT-MMTV mice to generate the PyMT-MMTVxHPSE-/- strain, providing us with a valuable in vivo model to characterise the role of HPSE in early mammary tumour development, tumour progression and metastasis. Our data indicate that although HPSE promoted angiogenesis, overall tumour development and metastasis between PyMT-MMTV and PyMT-MMTVxHPSE-/- mice remained comparable. The role of HPSE in the tumour microenvironment is defined further by using C57Bl/6xHPSE-/- mice. We demonstrate that the tumour stroma positively contributes to mammary tumour HPSE activity, promoting tumour angiogenesis. However, HPSE expressed by the tumour-bearing host appeared to play no significant role in tumour growth and metastasis. These data suggest that in certain cancers, HPSE may not play a significant role, in contrast to what has been proposed over the last two decades. This has significant implications in the development and administration of HPSE inhibitors to cancer patients.