The Role of Androgens in Prostate Physiology and Pathology

Summary

 This project is examining the specific sites and roles of androgen action involved in prostate mature prostate.

Supervisor(s)

Dr Ulla Simanainen, Professor David Handelsman

Research Location

Concord - ANZAC Research Institute

Program Type

Masters/PHD

Synopsis

Prostate cancer (PCa) is an androgen-dependent disease and constitutes a major health problem in Western countries now the second leading cause of cancer deaths in Australian men. Most men display signs of malignancy in the prostate at some point in their lifetime yet only a minority will suffer from overt PCa or die from it. This implies that crucial mechanisms operate slowly and are susceptible to interruption, if early stages of PCa development and progression are better understood. Furthermore, Nobel-prize winning work more than 60 years ago identified androgen deprivation, as still the only form of treatment for advanced incurable prostate cancer. Castration by medical or surgical means can halt PC progression temporarily and prolong life, but it cannot cure the disease and comes at a high price for men in deterioration their quality of life. Hence androgen action is critical to the development, progression and cure of prostate cancer. Yet, remarkably little is known about how testosterone initiates and promotes prostate cancer. Signaling via the androgen receptor (AR) is believed to be critical for carcinogenesis and progression of the disease. However exactly which cells and what signaling mechanisms are involved remained mysterious. Better understanding of androgen action on the prostate may lead to more effective prevention and treatment. For example, new treatments that interrupt androgen action only within the prostate without needing to cause androgen deficiency throughout the whole body would be a major advance. This goal requires better understanding of precise cell and tissue localization of androgen action in prostate. This however is a very challenging task because of intimate structural and functional relationship of epithelial and stromal tissue within the prostate. Fortunately new genetic tools have become available to undertake such research by inactivating AR selectively within specific tissues within the prostate.   This project is examining the specific sites and roles of androgen action involved in prostate mature prostate.  

1. Using the Cre-LoxP system develop mouse lines with fixed or inducible knockouts of the AR in the prostate epithelium and/or stroma. This work will allow us to examine whether androgens act primary via either tissue and how they then influence other prostate tissues. Using out unique transgenic mouse models we will gain new insight into the cell specific action of androgens within the prostate.
2. How functional AR signaling pathway is involved in the initiation, progression and eventually the terminal stage of androgen independent prostate cancer.

The project provides opportunity to gain extensive experience prostate physiology and pathology as well as in various laboratory techniques such as histology, immunohistochemistry, stereology, gene expression analysis. In addition, the student will get experienced in characterization of unique transgenic mouse models.  

Keywords

Prostate Cancer, Prostate, androgen, androgen receptor, transgenic models, Cre-LoxP technique, Cancer & leukaemia, Reproduction & development

Opportunity ID

The opportunity ID for this research opportunity is: 197