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The Role of Prolactin in the Cellular Response to DNA Damaging Agents

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The Role of Prolactin in the Cellular Response to DNA Damaging Agents University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2015-09-30 The Role of Prolactin in the Cellular Response to DNA Damaging Agents Karayazi Atici, Odul Karayazi Atici, O. (2015). The Role of Prolactin in the Cellular Response to DNA Damaging Agents (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28347 http://hdl.handle.net/11023/2567 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The Role of Prolactin in the Cellular Response to DNA Damaging Agents by Odul Karayazi Atici A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGICAL SCIENCES CALGARY, ALBERTA SEPTEMBER, 2015 © Odul Karayazi Atici 2015 Abstract High serum levels of the peptide hormone prolactin are associated with increased breast cancer risk and poor prognosis. Prolactin is also involved in breast cancer resistance to different chemotherapeutics. The overall goal of this project is to investigate potential pathways involved in prolactin induced resistance to DNA damaging agents with the hypothesis that the cross-talk between the prolactin pathway and the DNA damage response is important in the mechanism. We previously identified that one isoform of heat shock protein-90 (HSP90), Hsp90alpha, is a prolactin-Janus kinase-2 (Jak2)-signal transducer and activator of transcription-5 (Stat5) regulated gene in breast cancer cells. We have now observed that prolactin increased the viability of breast cancer cells to DNA damaging chemotherapeutics, and Hsp90 inhibitors, 17AAG and BIIB021, abrogated the effect of prolactin, indicating the mechanism of enhanced viability involves the master cancer chaperone Hsp90. The stability of Jak2 and both the total ataxia- telangiectasia mutated protein (ATM) and phospho-ATM appear to be dependent on functional Hsp90. Inhibition of Jak2 and ATM, with highly selective inhibitors (G6 and KU55933, respectively), abrogated prolactin enhanced viability, suggesting their role in prolactin induced cell viability. Drug combination experiments with Hsp90 inhibitor BIIB021 and doxorubicin, and ATM inhibitor KU55933 and doxorubicin, showed drug synergism between doxorubicin and both KU55933 and BIIB021 in MCF7 breast cancer cells. Interestingly, in orthotopic xenograft studies, autocrine prolactin from human breast cancer cells increased the tumor latency of doxorubicin induced DNA damaged cells in SCID mice compared to untreated or prolactin or doxorubicin alone. We hypothesize that this is in part due to the cross-talk of the prolactin and DNA damage response pathways that may be affecting the tumor microenvironment. ii Acknowledgements I would like to extend my gratitude and appreciation to my supervisor, Dr. Carrie S. Shemanko, for her guidance, patience and support during my research in her laboratory. Working in the Shemanko lab has given me invaluable and unforgettable experience. I would also like to thank the members of my committee, the past member Dr. Sung-Woo Kim and the current members Dr. Susan Lees-Miller and Dr. Hamid Habibi, who have provided me with valuable ideas and advices. I would like to extend my gratitude to Dr. David Hansen and Dr. Karl Riabowol for attending in my candidacy exam and to Dr. Catherine Too and Dr. Aru Narendran for attending in my defence exam. Thank you to all the past and the present members of the Shemanko lab. To Dr. Christian Perotti and the graduate students Anna Urbanska and Ashley Sutherland, for their guidance in the laboratory. I would like to thank Lin Su, for her endless help and valuable scientific discussions. I am highly grateful to Amanda Forsyth, for her friendship and support. I would especially like to thank to undergraduate students who worked directly on this project with me including Erin Marie Bell, Sara Mirzaei, Emilija Malogajski and Colin Stewart. Thank you to the supervisors and students of the Hansen, Habibi, Cobb, Moorhead, Buret and Chan laboratories for all their help and the use of their equipments. Thank you to all LESARC members for their support. I would especially like to thank to Dawn Martin and Mike Collier for their endless help during animal experiments. I would like to acknowledge the financial support of University of Calgary, Natural Sciences and Engineering Research Council of Canada (NSERC), Queen Elizabeth II Scholarships. The constant helps of the administrative staff Karen Barron and Sophia George are highly appreciated. iii Special thanks to all my family and friends. To my parents for always believing and supporting me. Very special thanks to my husband, Mehmet Atici, for his never-ending support and encouragement and, to my daughter and unborn son for passing me their infinite positive energy. iv Dedication To my aunts Yurdagul Uzun and Tulay Aktas, who could not win their battle with breast cancer. v Table of Contents Abstract............................................................................................................................... ii! Acknowledgements............................................................................................................ iii! Table of Contents............................................................................................................... vi! List of Figures and Illustrations ........................................................................................ xii! List of Symbols, Abbreviations and Nomenclature......................................................... xvi! ! 1.1 Breast cancer statistics...............................................................................................1! CHAPTER(ONE:1.2 The mammary(INTRODUCTION gland and mammary................................ gland microenvironment...........................................................................1! 1.2.1 Mammary gland overview.................................................................................1! 1.2.2 The mammary gland microenvironment ...........................................................3! 1.3 The hormone prolactin and its function in the mammary gland................................6! 1.3.1 Prolactin.............................................................................................................6! 1.3.2 Prolactin Receptor (PRLR)..............................................................................11! 1.3.3 Prolactin signalling pathways..........................................................................16! 1.3.3.1 Jak2- Stat5 Pathway...............................................................................16! 1.3.3.2 Ras-Raf-MAPK pathway.......................................................................19! 1.3.3.3 PI3K/ Akt pathway ................................................................................19! 1.4 Breast cancer and hormonal influence.....................................................................22! 1.4.1 Breast cancer classification .............................................................................22! 1.4.2 Treatment of breast cancer ..............................................................................23! 1.4.3 The role of estrogen in breast cancer...............................................................24! 1.4.4 The role of progesterone in breast cancer........................................................26! 1.4.5 The role of prolactin in breast cancer..............................................................27! 1.4.5.1 Epidemiologic studies highlight the role of prolactin in breast cancer..28! 1.4.5.2 In vivo studies implicating the role of prolactin in tumor formation.....30! 1.4.5.3 The role of prolactin in resistance to chemotherapy agents...................31! 1.4.5.4 Prolactin receptor antagonists................................................................32! 1.5 Heat shock protein 90 (Hsp90) ................................................................................34! 1.5.1 Chaperone mechanism of HSP90....................................................................35! 1.5.2 The role of Hsp90 in DNA damage response..................................................39! 1.5.3 The role of HSP90 in cancer and chemotherapy resistance ............................40! 1.5.4 Targeting Hsp90 in cancer treatment ..............................................................42! 1.6 DNA damage response ............................................................................................43! 1.6.1 DNA damage response overview ....................................................................43! 1.6.2 DNA repair mechanism...................................................................................44! 1.6.2.1 Base excision repair (BER)....................................................................44! 1.6.2.2 Mismatch repair (MMR)........................................................................44! 1.6.2.3 Nucleotide excision repair (NER)..........................................................45! 1.6.2.4 Double-strand break repair (DSB
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