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CYP17A1) Gene Variants for Their Steroidogenic Enzymatic Activities

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CYP17A1) Gene Variants for Their Steroidogenic Enzymatic Activities Functional Characterization of Cytochrome P450 17A1 (CYP17A1) Gene Variants for their Steroidogenic Enzymatic Activities by Cameron Phillip Capper A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmacology) in the University of Michigan 2016 Doctoral Committee: Associate Professor James M. Rae, Chair Professor Richard J. Auchus Professor Paul F. Hollenberg Associate Professor, Michael D. Johnson, Georgetown University Professor Yoichi Osawa Professor William Rainey Dedication To my Grandpa Phil ii Acknowledgements I would first like to thank my mentor, Dr. James Rae, for his guidance and mentorship during my years at Michigan. He has treated me like a colleague since my first day rotating in his lab, and I will forever be grateful of this respect. His perpetual optimism was tremendously valuable and his willingness to collaborate gave me the opportunity to expand my research horizons. I feel privileged to have had a committee so engaged in my research, interested in my ideas, and dedicated to my success. Because of this support I want to sincerely thank my committee members Drs. Paul Hollenberg, Yoichi Osawa, Richard Auchus, Michael Johnson, and William Rainey. Thank you to Dr. Hollenberg for inviting me to present at heme team meetings and for always being available to discuss data. Thank you to Dr. Osawa for sharing his expertise of ubiquitination and for his assistance with experimental design. Thank you to Dr. Auchus, and Auchus lab members, Hwei-Ming Peng, Jiayan Liu, and Shigehiro Karashima, for patiently training me to use the lab equipment and assisting me with interpreting data. Thank you to Dr. Johnson for making time to fly in for committee meetings and supporting my research from afar via email. Thank you to Dr. Rainey for agreeing to share his expertise and serve on my committee on such little notice. iii I would especially like to thank the members of the Rae lab, chiefly Christina Gersch and Dr. Jose Larios. They have been instrumental in my development as a scientist by helping to trainingme and by answering a lot of my questions. Special thanks to Drs. Dan Hayes and Lynn Henry for sharing their clinical expertise and helping me to see the bigger picture of my research. I would like to extend a heartfelt thank you to my parents, Barry and Karen, and my sister, Bailey, for their unconditional love and support. Finally, I’m abundantly thankful for my wife, Kayla, whom I met here at Michigan. She has been a constant source of encouragement, love, and happiness. iv Table of Contents Dedication ..................................................................................................................................... ii Acknowledgments ....................................................................................................................... iii List of Figures ............................................................................................................................. vii List of Tables ............................................................................................................................... ix List of Abbreviations .................................................................................................................... x Chapter I. Introduction .................................................................................................................1 Normal Physiology .....................................................................................................................2 Hypothalamic-Pituitary-Adrenal Axis .....................................................................................2 Adrenal Steroidogenesis ..........................................................................................................2 Hypothalamic-Pituitary-Gonadal Axis ....................................................................................4 Gonadal Steroidogenesis ..........................................................................................................5 Peripheral Steroid Metabolism ................................................................................................6 Nuclear Hormone Receptor Signaling .....................................................................................7 Estrogens and Breast Cancer ....................................................................................................8 Estrogen Receptor and Breast Cancer ......................................................................................8 Pathways of Estrogen Synthesis in Breast Cancer ...................................................................9 Estrogen Receptor Antagonists ..............................................................................................10 Aromatase Inhibitors ..............................................................................................................12 Androgens and Prostate Cancer .............................................................................................13 Androgen Receptor and Prostate Cancer ...............................................................................13 Pathways of Androgen Synthesis Prostate Cancer ................................................................14 Targeting of Androgen Synthesis and Action in Prostate Cancer .........................................17 CYP17A1 inhibition ..............................................................................................................18 Alternative pathways to steroid receptor activation .............................................................21 CYP17A1 inhibitors in breast cancer ....................................................................................22 Androgen receptor-positive triple negative breast cancer .....................................................23 Rationale for Thesis .................................................................................................................24 References .................................................................................................................................30 v Chapter II. The CYP17A1 inhibitor abiraterone exhibits estrogen receptor agonist activity in breast cancer ............................................................................................................................40 Introduction ..............................................................................................................................40 Methods .....................................................................................................................................42 Results .......................................................................................................................................44 Discussion .................................................................................................................................47 References .................................................................................................................................56 Chapter III. CYP17A1 expression in MCF-7 breast cancer cells accurately models steroidogenesis and can be used as a tool to identify inhibitors of sex steroid synthesis ......61 Introduction ..............................................................................................................................61 Methods .....................................................................................................................................63 Results .......................................................................................................................................66 Discussion .................................................................................................................................71 References .................................................................................................................................82 Chapter IV. Functional characterization of the D216H and G162R CYP17A1 genetic variants..........................................................................................................................................85 Introduction ..............................................................................................................................85 Methods .....................................................................................................................................87 Results .......................................................................................................................................90 Discussion .................................................................................................................................94 References ...............................................................................................................................106 Chapter V. Conclusions and Future Directions ......................................................................109 Discussion ...............................................................................................................................109 References ...............................................................................................................................116 Appendix .....................................................................................................................................119 vi List of Figures Figure 1.1. Adrenal
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