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Identification and characterization of proteins that interact with the androgen receptor to modulate its activity

University of British Columbia

Prostate cancer is among the most frequently diagnosed malignancies and one of the leading causes of cancer-related death in Canadian men. Prostate tumours are initially dependent on androgens for growth and survival. At this early stage of disease, androgen ablation therapy is an effective treatment but ultimately results in progression to the lethal androgen independence (AI) phase. Androgens exert their effects through the androgen receptor (AR), which is a ligand-activated transcription factor that plays a central role in prostate cancer development. Therefore, proteins that interact with AR and modify its activity may also be associated with the progression of disease to AI. The overall goal of the research described in this thesis is to gain a more comprehensive understanding of the mechanism by which AR regulates gene transcription during prostate cancer progression. Initial studies focused on the identification of proteins that interact with the unique N-terminal domain (NTD) of AR, which may confer receptor-specific responses. Due to the challenges of utilizing the AR-NTD for analysis in conventional yeast two-hybrid assays, the repressed transactivator (RTA) system was employed as a novel approach to identify AR-binding proteins. Several previously unknown AR-protein interactions were found, which were confirmed through in vitro biochemical assays and in prostate cancer cells. The role of the most frequently detected AR-binding protein from the RTA system, L-dopa decarboxylase (DDC), in modulating AR activity was assessed using transactivation assays. DDC was found to be a coactivator of AR that enhanced receptor transcriptional activity in vitro and in vivo . Further mechanistic studies revealed that DDC facilitates AR ligand binding and requires its enzymatic activity for coactivation function. The relevance of DDC to disease was then examined using a clinical prostate cancer progression model. DDC was found to be co-expressed with AR in neuroendocrine-phenotype adenocarcinoma cells and its expression increased in hormone-treated prostate tumours, as well as in Al disease, suggesting that this coactivator may sustain aberrant AR activity during prostate cancer progression. Overall, the research presented in this study furthers our understanding of the role of coregulators in mediating AR activity and their potential importance in progression of disease.

Text

2011-02-23

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http://hdl.handle.net/2429/31705

Pathology

University of British Columbia

Graduate