| PQBP1
ISOFORMS IN PROSTATE CANCER.
Dr Charlotte Bevan Imperial College London, Department of Oncology |
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Prostate cancer is the most commonly diagnosed cancer in Western males and its incidence is increasing. As prostate tumour growth is initially dependent on androgens such as testosterone, several therapeutic agents oppose the action of androgens hence are termed antiandrogens. Androgens transmit their growth‑promoting signals via a key protein called the androgen receptor; androgens bind to and activate this protein while antiandrogens also bind to it but inhibit its activity.
The mechanisms by which they do this are not clear. While initially successful, treatment with antiandrogens inevitably fails and there are no effective treatments for the advanced, metastatic stage of the disease that follows. It is therefore vital that we understand the mechanisms by which antiandrogens work in order to avoid or delay this failure. This knowledge will also enable us to understand why antiandrogen therapies fail and, importantly, design new second‑line therapies for use when this happens.
It is known that androgen receptor recruits inhibitory proteins called corepressors when antiandrogens are bound, but it is not clear which corepressors are required in human tumours for antiandrogens to be effective. We have identified a novel corepressor, PQBP1, which is the first to show the pattern of recruitment consistent with a clinical role in antiandrogen action, being recruited to the androgen receptor ligand‑binding domain in the presence, but not absence of antiandrogens. Further, PQBP1 strongly inhibits androgen receptor activity. This protein exists in at least 4 distinct forms, which contain different functional domains.
This study will characterise the expression of the different forms of PQBP1 in normal prostate and prostate tumours, to determine their potential as markers for aggressive disease. We will study the effects of the different forms on androgen receptor activity, and their ability to enhance antiandrogen actions, i.e. potential use in adjuvant therapies to increase the relapse‑free period and hence life expectancy of patients.
Progress:
The first interim
progress report (.pdf file) is available here.
Research interim report, 27 March 2008.
Project 2006/11