Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

CRISP3 regulates progression from in situ to invasive prostatic adenocarcinoma (#24)

Marianna Volpert 1 , Duangporn Jamsai 1 , Rebecca D'Sylva , John Pedersen 2 , Gail Risbridger 1 , Peter McIntyre 3 , Luc Furic 1 , Moira O'Bryan 1
  1. Monash University, Clayton, VIC, Australia
  2. TissuPath, Mount Waverley, VIC, Australia
  3. RMIT University, Bundoora, VIC

Introduction: One of the most challenging aspects of prostate cancer diagnosis is predicting whether cancer will remain indolent or progress to invasive, aggressive and potentially lethal disease. Current markers such as PSA are unreliable and tumours requiring treatment may remain undetected while others are over-treated. CRISP3 is a member of a poorly defined family of proteins that is highly up-regulated in human prostate cancer and controversially proposed as a prognostic marker. As a major focus of my PhD, we sought to define the role of CRISP3 in the molecular pathology of prostate cancer through the generation of a Crisp3 knockout mouse line, which was crossed onto the Hi-MYC mouse model of prostatic adenocarcinoma.

Results: As in the healthy human prostate, CRISP3 was not expressed in the wild type mouse prostate, but was up-regulated 800-fold in Hi-MYC lateral prostate tumours from 5-7 months old males. Over-expression coincided with cancer invasion in 6 of 8 Hi-MYC+Crisp3+/+ animals. In contrast, Crisp3 deletion completely prevented the progression from carcinoma in situ to invasive disease (n=9). Furthermore, CRISP3 production accelerated the transition from high-grade PIN to carcinoma in situ, and Crisp3 knockout decreased tumour mass as measured by c-MYC immunohistochemistry (p=0.0228).

Conclusions: We show that CRISP3 expression was required for the transition from in situ to invasive carcinoma in the Hi-MYC mouse model. These findings demonstrate for the first time that CRISP3 is pro-tumorigenic by driving prostate cancer invasiveness, making CRISP3 a plausible biomarker and therapeutic target in human prostate cancer.