Endocrine Abstracts

Prostate growth during development and at puberty is dependent on androgens. After puberty, growth ceases and the secretory function of the organ is maintained in the presence of high circulating testosterone levels. However, in cases of benign prostatic hyperplasia and prostate cancer, growth resumes inappropriately. Like normal prostate growth, tumour growth is initially androgen-dependent; hence, treatment involves removing circulating androgens by chemical castration and opposing their action using antiandrogens. Antiandrogen treatment is initially effective in the majority of cases. However, at a median of 13 months from the initiation of hormonal therapy, patients show biochemical evidence of relapse. Symptomatic relapse occurs 2 years later followed by death within a median of 7 months. There is currently no effective treatment for this 'androgen-independent' stage of the disease. In order to understand both why hormone-dependent growth resumes in cases of prostate cancer, and why current hormonal therapies eventually fail, we need a more complete understanding of the mode of action of androgens and antiandrogens in the prostate.
Proteins regulated by the androgen receptor may be involved in prostate cancer formation, and be of use as second line therapeutic targets once hormone therapy fails. We are using proteomics to investigate the effect of androgens on prostate cancer cells, in order to identify proteins involved in androgen-stimulated growth pathways. Analysis of regulated proteins has identified mitochondrial proteins and proteins involved in antioxidant defence, cell cycle regulation and possibly apoptosis.
We are also using a functional proteomics approach to produce a global picture of proteins that interact with the androgen receptor in vivo when prostate cancer cells are treated with androgens and antiandrogens. Tracking androgen receptor through the cell, we have found that different antiandrogens appear to block androgen receptor signalling via different mechanisms, targeting the receptor to specific sub-compartments of the cytoplasm or nucleus.