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Role of heat shock protein 27 and Lyn tyrosine kinase in regulation of androgen receptor expression and activity in prostate cancer

University of British Columbia

Prostate Cancer (PCa) is the most common male cancer and the second leading cause of cancer‐related deaths in North America. While many gains have been made in early detection and treatment of localized PCa, many men still die of the metastatic disease. Androgen ablation therapy remains the most effective therapy for patients with advanced disease. While ~80% of patients respond initially to this treatment, most patients progress to Castrate Resistant Prostate Cancer (CRPC) stage. Current literature indicates that CRPC tumours are not uniformly hormone refractory and may remain sensitive to therapies directed against the AR axis. Therefore, several new classes of AR‐targeting agents are now in clinical development, including more potent AR antagonists (MDV3100) and inhibitors of steroidogenesis (abiraterone). Although enthusiasm for this approach remains high, prostate tumour heterogeneity and the inevitable development of resistance dictates a critical need to better understand the mechanisms of resistance in which AR remain active. In the current doctoral thesis role of heat shock protein (Hsp) 27 and Lyn tyrosine kinase in regulation of AR protein expression was investigated. The central hypothesis is that increased expression and activity of Hsp27 and Lyn kinase stabilizes and activates AR protein and leads to prostate cancer progression through promoting prostate cancer cell survival. Three specific objectives were accomplished in this thesis. First, the relationship between Hsp27 and AR was studied. To this end, it was demonstrated that expression and activity of Hsp27 via a nongenomic mechanism regulates AR protein stability, shuttling and transcriptional activity. In the next step, the underlying molecular mechanisms through which Lyn tyrosine kinase regulates AR activity in the castrated environment was investigated. The experiments demonstrated that Lyn kinase regulates AR protein expression and transcriptional activity and that it plays a key role in PCa progression to the castrated resistant stage. Finally, a novel role for Lyn kinase in Epidermal Growth Factor‐mediated (EGF‐mediated) AR activity was defined. The results obtained in this thesis defined new pathways involved in regulation of AR protein stability and justified further investigation of Hsp27 and Lyn kinase as therapeutic targets for CRPC.

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2013-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42114

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/