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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

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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 ROLE OF HEAT SHOCK PROTEIN 27 AND LYN TYROSINE KINASE IN REGULATION OF ANDROGEN RECEPTOR EXPRESSION AND ACTIVITY IN PROSTATE CANCER by Anousheh Zardan A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2012 © Anousheh Zardan, 2012 Abstract 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 ii 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. iii Preface The publications presented in this thesis are based on the work that I carried out towards the completion of my PhD program. Manuscripts listed in this thesis either have already been published or will be submitted for publication as co‐authored works. A version of chapter 2 of this thesis has been published in Cancer Research as noted below: Chapter 2: Cooperative interactions between androgen receptor and Hsp27 facilitate AR transcriptional activity. Amina Zoubeidi, Anousheh Zardan, Eliana Beraldi, Ladan Fazli, Richard Sowery, Paul S. Rennie, Colleen C. Nelson, Martin E. Gleave, Cancer Research. 2007 Nov 1;67(21):10455‐65. Dr. Martin Gleave was the principal investigator of this manuscript. The main idea of studying the interaction between Hsp27 and AR was introduced by Dr. Amina Zoubeidi. I designed and performed all the in vitro experiments to demonstrate a) the interaction between AR/Hsp27 and b) the role of Hsp27 on AR protein stability. Dr. Amina Zoubeidi designed and performed all the experiments to demonstrate the role of Hsp27 on AR transcriptional activity (transactivation assays, immunofluorescence, EMSA). Mrs. Eliana Beraldi performed the ChIP analysis. Ms. Virginia Yago and Ms. Mary Bowden helped with the in vivo experiments. Preparation and analysis of protein samples from tumours was done by myself. Dr. Ladan Fazli, the research pathologist at the Vancouver Prostate Centre, was involved in the analysis of all the immunohistochemistry staining of prostate tissues. Dr. Amina Zoubeidi iv drafted the manuscript and finalized it for publication. Dr. Richard Sowery, Dr. Paul Rennie, Dr. Colleen Nelson and Dr. Martin Gleave reviewed the work and provided insightful comments. Chapter 3: Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate resistant prostate cancer. Anousheh Zardan, Eliana Beraldi, Ladan Fazli, KaMun Nip, Michael E. Cox, Martin E. Gleave and Amina Zoubeidi. A version of chapter 3 will be submitted for publication. Dr. Amina Zoubeidi was the principal investigator for the manuscript. All the in vitro and in vivo experiments performed in this chapter were designed, performed and analyzed by myself and reviewed by Dr. Amina Zoubeidi and Dr. Michael Cox. Ms. Kamun Nip provided some help with the initial western blot analysis and Mrs. Eliana Beraldi performed the caspase‐ 3 activity assay. Ms. Virginia Yago and Mr. Igor Moskalev were involved in mice bleeding. Dr. Ladan Fazli analyzed all of the immunohistochemistry staining of the prostate tissues. Dr. Martin Gleave reviewed the data and provided helpful comments. The manuscript was drafted by myself and reviewed by Dr. Amina Zoubeidi, Dr. Michael Cox and Dr. Martin Gleave. Chapter 4: Lyn tyrosine kinase promotes castration resistant prostate cancer progression through EGF‐mediated phosphorylation of androgen receptor. Anousheh Zardan, Eliana Beraldi, Martin Gleave, Michael Cox, Amina Zoubedi. A version of chapter 4 will be submitted for publication. Dr. Amina Zoubeidi is the principal investigator of this manuscript. All the experiments in this chapter were designed, performed and analyzed by myself, Anousheh Zardan, and reviewed by Dr. Amina Zoubeidi. Mrs. Eliana Beraldi helped with the caspase‐3 activity assay. The manuscript was drafted by myself and reviewed by Dr. Amina Zoubeidi, Dr. Michael Cox and Dr. Martin Gleave. v The work presented in this thesis has been carried out with the approval of the University of British Columbia Animal Care and Ethics Board Committees under the following certificate numbers respectively: A10 – 0165, 4597 – 11. vi Table of Contents Abstract ................................................................................................................................ii Preface ................................................................................................................................ iv Table of Contents ............................................................................................................... vii List of Figures ....................................................................................................................... x List of Abbreviations .......................................................................................................... xii Acknowledgements ........................................................................................................... xvi CHAPTER 1: Introduction ................................................................................................. 1 1.1 The Prostate ...................................................................................................................... 1 1.1.1 Origin, Anatomy and Function ................................................................................................... 1 1.1.2 Histology and Cells ..................................................................................................................... 2 1.2 Androgens ......................................................................................................................... 5 1.2.1 Production, Function and Metabolism ....................................................................................... 5 1.3 Androgen‐Receptor (AR) ................................................................................................... 8 1.3.1 Structure, Biology and Function ................................................................................................. 8 1.3.2 AR Co‐Regulators (Co‐activator and Co‐Repressors) ............................................................... 12 1.4 Prostate Cancer (PCa) ..................................................................................................... 13 1.4.1 Development ............................................................................................................................ 13 1.4.2 Epidemiology and Risk Factors ................................................................................................. 13 1.4.3 Diagnosis and Prognosis ........................................................................................................... 15 1.5 Treatment ....................................................................................................................... 17 1.6 Development of Castration Resistant Prostate Cancer (CRPC) ....................................... 21 1.7 Chaperone Proteins ........................................................................................................ 27 1.7.1 Biology and Function ................................................................................................................ 27 1.7.2 Small Heat Shock Proteins (sHsps) ..........................................................................................
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