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Apoptotic Actions of Estrogen Receptor Β in Prostate Cancer

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Apoptotic Actions of Estrogen Receptor Β in Prostate Cancer Antiproliferative and pro-apoptotic actions of Estrogen receptor β in prostate cancer A Dissertation Presented to the Faculty of the Department of Biology and Biochemistry University of Houston In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy By Prasenjit Dey May 2013 Antiproliferative and pro-apoptotic actions of Estrogen receptor β in prostate cancer Prasenjit Dey APPROVED: Dr. Jan-Åke Gustafsson, Chairman Dr. Anders M. Ström Dr. Robert Schwartz Dr. Paul Webb Dr. Yuhong Wang Dr. Dan Wells, Dean, College of Natural Sciences and Mathematics ii Dedicated to my parents, brother, sister and my beloved wife for their support and encouragement. iii Acknowledgements I would like to express my sincere thanks to my advisor, Dr. Jan-Åke Gustafsson, for giving me the opportunity and his relentless guidance, encouragement, support, and valuable inputs throughout this endeavor. I would also like to thank him especially for the valuable inputs towards my dissertation. His readiness to discuss the progress of the work and expert suggestions helped me to complete the studies. I am also immensely thankful to my co-supervisor Dr. Anders M Ström. In many of the conversations we have had over the last three and half years, he generously shared with me his deep insight about estrogen receptor and its impact on cancer. I would also like to thank him for his extreme patience in listening to every single question I came up with and providing immensely helpful solutions. Without his time and effort, completion of all this work would have been impossible. I would also like to sincerely thank my committee members Dr. Robert Schwartz, Dr. Paul Webb, and Dr. Yuhong Wang. Their time, suggestions and patience have been very helpful. I am also immensely thankful to Dr. Margaret Warner for her relentless suggestions and help in many of my experiments. The friendly and co-operative working environment at the Center for Nuclear Receptors and Cell Signaling (CNRCS) was a great help, during all the years, I have spent here. I would like to thank Dr. Daniel Frigo, Dr. Shaun Zhang, Dr. Cecilia Williams, Dr. Sang-Hyuk Chung, Dr. Chin-Yo Lin, and Dr. Christophoros Thomas, who never hesitated in sharing their expertise on nuclear receptor and cancer biology iv and gave extremely valuable suggestions whenever needed. I also want to extend my thanks to my friends in the lab, Fotis, Efi, Selvaraj, Geeta, Armando, Gayani, Ryan, Alicia, Laure, Leena, Sabrina, Rodrigo, Fu, Igor, Lakshmi, Ruxin, Shana, Sharanya, Kim, Shana, Trung, Anne, Jun, Ka, Jenny, Sreedevi, Nick, Jin, and Caroline. Thanks to other members of our lab, who have helped me with my dissertation. I would also like to specially thank Anthony, for his assistance in many of my experiments. Special thanks to all my friends in Houston, Arun, Monal, Bhoom, Shravani, Raj, Meenu, Ritu, Rajib, and Anupam for being there always. It is because of them that I never felt I was thousands of miles away from home. This journey would have been impossible without the support from my family. I am indebted to my grandparents, for the love they showered on me. My dad inspired me with his optimism towards everything and helped me in realizing my aspirations by constant encouragement. My mom has been the most important influence in my life. It is impossible to describe her contribution in a few words. Her excellent vision and deeply thought suggestions have helped me in becoming what I am now. Thanks also to my sister Soma for making my life happy and cheerful and my brother Jayanta for his constant support and guidance. I would also like to thank Aditi and Surajit(da) for being part of our family. I would also like to thank my parents-in-law for being so friendly and understanding. Lastly, thanks to my dear wife Nganbiton (Anna), who has always extended her helping hands. Her love, comfort, and support throughout these years helped me v to achieve my goals. I would like to thank her for being my closest friend and my deepest love. This work was supported by CPRIT grant HIRP100680 and RP110444, the Texas Emerging Technology Fund under Agreement no. 300-9-1958, the Robert A. Welch Foundation (E-0004) and the Swedish Cancer Fund. vi Antiproliferative and pro-apoptotic actions of Estrogen receptor β in prostate cancer An Abstract of a Dissertation Presented to the Faculty of the Department of Biology and Biochemistry University of Houston In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy By Prasenjit Dey May 2013 vii Abstract High Gleason grade prostate cancers are aggressive. Currently, the major target for treatment is the androgen receptor. Recent literature points towards a tumor suppressive role of estrogen receptor β (ERβ), which has a potential to be exploited as a target for novel therapeutics used for treatment of prostate cancer. In Chapter 2 of the thesis, we showed that ERβ-selective agonists elicited an increase in apoptosis and this was accompanied by an increase in expression of the pro-apoptotic factor PUMA. Induction of PUMA was dependent on the presence of the transcription factor FOXO3 but was independent of p53. In the ventral prostates of ERβ-/- mice, expression of FOXO3a is lower than that in WT littermates demonstrating a relationship between ERβ and FOXO3a expression found in PC3 and LNCaP cells. Furthermore, in prostate cancers of Gleason grade 4 or higher there was a marked reduction of both ERβ and FOXO3a, while both genes were well expressed in BPH sections. In Chapter 3 of the thesis, we investigated whether the loss of ERβ (also called as ERβ1) and/or expression of its splice variant ERβ2 affected signaling pathways involved in proliferation and bone metastasis of prostate cancer. We found repressed expression of the bone metastasis regulator Runx2 and its target gene, Slug by ERβ1. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate cancer, was increased by ERβ2. In terms of cell cycle modification, of the two receptors, ERβ1, but not ERβ2, inhibited proliferation and expression of the proliferation markers Cyclin E, c-Myc, and p45Skp2. Xenograft studies using athymic nude mice confirmed the proliferative viii effect of ERβ2, as tumors in mice bearing PC3-ERβ2 cells were substantially larger than tumors in mice bearing PC3-control and PC3-ERβ1 cells. ix Table of Contents Acknowledgements .................................................................................................................................. iv Abstract ...................................................................................................................................................... viii Table of Contents ....................................................................................................................................... x List of Figures .......................................................................................................................................... xiv List of Tables ............................................................................................................................................ xvi List of Abbreviations ............................................................................................................................ xvii Chapter 1: General introduction .......................................................................................................... 1 1.1 Prostate cancer .................................................................................................................................... 2 1.1.1 Prostate cancer pathogenesis ............................................................................................... 2 1.1.2 Prostate cancer diagnosis ....................................................................................................... 4 1.1.3 Prostate cancer treatment ..................................................................................................... 5 1.2 Hormones and transcription factors .......................................................................................... 5 1.2.1 Nuclear receptors ...................................................................................................................... 6 1.2.2 Androgens and androgen receptor (AR) ...................................................................... 10 1.2.3 Role of estrogen in prostate ............................................................................................... 14 1.2.4 Estrogen receptor (ER) ........................................................................................................ 15 1.2.5 Mechanism of ER action ....................................................................................................... 20 1.3 Estrogen receptor β and prostate cancer .............................................................................. 21 1.3.1 Overview of estrogen receptor β ...................................................................................... 21 1.3.2 Role of ERβ as an anti-proliferative factor ................................................................... 24 1.3.3 ERβ and apoptosis .................................................................................................................. 27 1.3.4 ERβ’s role in invasion and epithelial mesenchymal transition (EMT) ............ 29 1.3.5 ERβ’s role in hypoxia and energy metabolism ..........................................................
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