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Genetic Variations Associated with Resistance to Doxorubicin and Paclitaxel in Breast Cancer

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Genetic Variations Associated with Resistance to Doxorubicin and Paclitaxel in Breast Cancer GENETIC VARIATIONS ASSOCIATED WITH RESISTANCE TO DOXORUBICIN AND PACLITAXEL IN BREAST CANCER by Irada Ibrahim-zada A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto © Copyright by Irada Ibrahim-zada 2010 ii Genetic variations associated with resistance to doxorubicin and paclitaxel in breast cancer Irada Ibrahim-zada Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto 2010 Abstract Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance. This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). iii Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. A constructed interactome suggested that there is cross-talk at the Nrf-2 oxidative stress pathway between genes associated with resistance to doxorubicin and paclitaxel. This unique GWA approach serves as a proof-of-principle study and systematically investigates targets responsible for variable response to chemotherapy in breast tumor cells and possibly the tumors of breast cancer patients. Overall, the model discovered novel candidate genes that have not been previously associated with doxorubicin and paclitaxel cytotoxicity. Future studies will be directed at illustrating a causative relationship between the observed genomic changes and drug resistance in breast cancer patients undergoing doxorubicin and paclitaxel chemotherapy. iv To my parents: My mom, Leylakhanim, who sacrificed her PhD candidacy for her family, for her children to accomplish it. My dad, Tofig, who is my role model in my academic endeavors. Explore. Dream. Discover. Mark Twain v Acknowledgments To many people who showed support and inspired me during my graduate studies, I would like to express my sincere thanks. I express my gratitude to my supervisor, Dr. Hilmi Ozcelik and my co-supervisor Dr. Kathleen I. Pritchard, for their guidance, advice and encouragement. I have learned so much, and without you, this would not have been possible. Your support was invaluable. I would also like to thank my thesis committee advisors, Dr. Amadeo M. Parissenti (Sudbury, ON) and Dr. Steven Gallinger, who went above and beyond their duties throughout the project for their insight, support and collaboration. I would like to extend my gratitude to people of Ozcelik lab who have been an essential part of my graduate life and have enriched my time in Canada. The special thanks go to Dr. Sevtap Savas and Dr. Hamdi Jarjanazi who introduced me to this research project and supported me as a part of a team. I would like to thank Susan Lau, Priscilla Chan, Lynda Doughty, and Joyce Keating for advice and support, for making my time in the lab a great learning experience and for providing a friendly atmosphere. I wish to thank summer research students, Andras Lindenmaier, Lawson Eng, and Melda Esendal who helped me to carry out my project. I am grateful to my fellow graduate students for their help and advice: Dr. George Charames, Dr. Sheron Perera, Dr. Miralem Mrkonjic, Stewart Cho, Ken Kron, and Eric Tram. I am indepted to Dr. Amadeo Parissenti‟s laboratory and to many people from Sudbury Regional Cancer Centre for support and friendship, without which completion of this work would not have been possible. Most notably, I would like to extend my thanks to Dr. Stacey Santi, Dr. Julia Romeros, and Jane Vanderklift for all the help I received, for endless hours and support, for always being within reach when I needed guidance. Finally, I would like to thank my family and friends for their love, support and unwavering confidence in me. To my Mom and Dad: your unconditional love, support and encouragement throughout the years have allowed me to be where I am today. You have been with me every step of the way, through good times and bad, since I left my home in Azerbaijan to study in vi Canada. You instilled in me the confidence that I am capable of doing anything I put my mind to. To my brother, Orhan, thank you for encouragement and endless patience. I would like to acknowledge the support of the Canadian Breast Cancer Foundation (2008-2011), the University of Toronto Open Fellowship Award (2008-2010), University Health Network Medical Staff Association, the Canadian Institutes of Health Research (MOP-89993), the Ontario Institute for Cancer Research (02May-0159), and the Northern Cancer Research Foundation. vii Table of Contents Acknowledgments............................................................................................................................v Table of Contents .......................................................................................................................... vii List of Tables ................................................................................................................................. xi List of Figures .............................................................................................................................. xiii Abbreviations .................................................................................................................................xv Chapter 1 Introduction .....................................................................................................................1 1 Introduction and Literature Review ............................................................................................1 1.1 Chapters content...................................................................................................................1 1.2 Breast cancer ........................................................................................................................2 1.3 Molecular portraits of breast cancer ....................................................................................4 1.4 A new treatment paradigm: pharmacogenomics ..................................................................6 1.5 Pharmacogenomics in breast cancer ....................................................................................7 1.6 Single nucleotide polymorphism and Genome-wide Association Studies ..........................8 1.7 Cancer cell lines .................................................................................................................10 1.8 Hypothesis & Objectives: ..................................................................................................10 1.8.1 Hypothesis..............................................................................................................10 1.8.2 Aims .......................................................................................................................11 Chapter 2 Anthracyclines and Taxanes..........................................................................................13 Abstract .....................................................................................................................................13 2 Antracyclines and Taxanes .......................................................................................................14 2.1 Drug resistance in breast cancer ........................................................................................14 viii 2.2 Doxorubicin: ......................................................................................................................16 2.2.1 Biology of the potentially modulated target pathways ..........................................16 2.2.2 Mechanisms of Resistance: ....................................................................................17 2.3 Paclitaxel: ...........................................................................................................................20 2.3.1 Biology ...................................................................................................................20 2.3.2 Mechanisms of resistance ......................................................................................20 2.4 Genome-Wide Association Studies of Resistance to Doxorubicin and Paclitaxel ............24 2.4.1 Doxorubicin: ..........................................................................................................24 2.4.2 Paclitaxel: ...............................................................................................................31 2.5 Influence of the genome-wide
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