Oral Presentation Matrix Biology Society of Australia and New Zealand Annual Meeting 2012

Role of Adamts1 and cleaved versican in mammary tumour growth and metastasis  (#6)

Carmela Ricciardelli 1 , K M Frewin 1 , I A Tan 1 , E D Williams 2 , K Opeskin 3 , M A Pritchard 4 , W V Ingman 1 , D L Russell 1
  1. School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia
  2. Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia
  3. Department Anatomical Pathology, St Vincent’s Hospital , Melbourne, Victoria, Australia
  4. Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia

The Adamts1 protease is commonly upregulated in metastatic carcinoma and its overexpression in cancer cells promotes experimental metastasis.  However, whether Adamts1 is essential for metastatic progression is unknown. To clarify this role we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumour model in Adamts1knockout mice.  Adamts1-/-/PyMT mice displayed significantly reduced mammary tumour burden and increased survival compared to their wildtype and heterozygous littermates.  Importantly, lung metastatic burden was significantly reduced in Adamts1-/-/PyMT mice.  Histological examination revealed an increased proportion of tumours with ductal carcinoma in situ and a lower proportion of high grade invasive tumours in Adamts1-/-/PyMT mice compared to Adamts1+/+/PyMT mice.  Increased apoptosis with unaltered proliferation and vascular density in the Adamts1-/-/PyMT tumours suggested that reduced cell survival accounts for the lower tumour burden in Adamts1 deficient mice. Furthermore Adamts1-/- tumours had significantly reduced cleaved versican.  Increased numbers of CD45+ leukocytes in the stroma of Adamts1-/- tumours and characterisation of immune cell gene expression indicated that cytotoxic cell activation was increased in Adamts1-/- vs Adamts1+/+ tumours.  This finding is supported by significantly elevated IL12+ cell numbers in Adamts1-/- tumours.  This study provides in vivo evidence that Adamts1 specifically promotes mammary tumour growth and progression to metastasis in the PyMT model and is a potential therapeutic target to prevent metastatic breast cancer.