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A Dissertation Entitled Novel Actions of Steroid Receptors That Limit A Dissertation Entitled Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers by Mugdha Patki Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Science Dr. Manohar Ratnam, Committee Chair Dr. Ivana de la Serna, Committee Member Dr. Stephan M. Patrick, Committee Member Dr. Edwin R. Sanchez, Committee Member Dr. Robert J. Trumbly, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo December 2013 Copyright 2013, Mugdha Patki This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers by Mugdha Patki Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Science The University of Toledo December 2013 The primary physiological role of estrogens is the development of secondary sexual characteristics including development and function of the normal breast, reproductive system, bone homeostasis, cognitive functions and cardiovascular system. Estrogen has also been implicated as a major player in the progression of normal breast epithelial tissue to a carcinoma. The role of estrogens in breast cancer has been studied extensively and mainly attributed to the transcriptional activation of growth genes through the estrogen receptor. Along with activation of genes, estrogen is also responsible for repression of many genes. Anti-estrogens antagonize both gene activation and gene repression by estrogen. However, the significance and physiological relevance of gene repression by estrogen is poorly understood. mRNA profiling of MCF-7 breast cancer cells combined with a detailed gene ontology analysis revealed that the genes repressed by estrogen are mostly involved in tumor progression including invasion, drug resistance, angiogenesis and immune evasion. This study looks at the mechanism and impact of estrogen in repressing these tumor progression genes in breast cancer cells; we found that iii estrogen suppresses the invasiveness of breast cancer cells in a manner that is antagonized by anti-estrogens and is independent of HER2 status. These studies have implications in understanding the incidence of invasive breast cancer following hormone replacement therapy and long term anti-estrogen treatment and may also aid in the development of superior drugs for adjuvant treatment in breast cancer. Variability in response to chemotherapeutic drugs among patients is a longstanding issue in the treatment of several cancers. Likewise, in advanced lung cancer, patient response to the recently introduced drug, pemetrexed is variable. Pemetrexed is an antifolate approved for the first-line treatment of advanced non-squamous non-small cell lung cancer. Dexamethasone was added to the treatment regimen with pemetrexed to alleviate the serious side effect of severe skin rash observed in many patients. Dexamethasone is administered to patients the day before, the day of and the day after pemetrexed chemotherapy. We show that treatment of non-squamous non-small cell lung cancer cell line models with dexamethasone causes a reduction in the S-phase fraction of cells along with a decrease in the expression of thymidylate synthase and dihydrofolate reductase, which are primary and secondary targets of pemetrexed, respectively. As a consequence of these effects of dexamethasone pemetrexed cytotoxicity is attenuated. The response to dexamethasone is variable among different cell line models. Our correlative and functional studies demonstrate that the variability in pemetrexed sensitivity is causally related to variability in the expression of the glucocorticoid receptor isoform alpha, i.e. cells with relatively lower expression of the receptor fail to respond to dexamethasone iv and hence are sensitive to pemetrexed. These results could help to predict response to pemetrexed therapy leading to the development of individualized treatment strategies. v I lovingly dedicate my dissertation to my parents, Minal and Rajiv Patki, for always supporting my dreams and for their endless love and faith in my abilities. To my maternal grandfather, Ratnakar Mohile and to the memory of my maternal grandmother, Vimal Mohile, for being a source of inspiration and encouragement to me throughout my life. To my paternal grandmother, Asha Patki and to the memory of my paternal grandfather, Nilkanth Patki, for teaching me the importance of education and hard work. vi Acknowledgements I would like to thank my advisor Dr. Manohar Ratnam whose eternal wealth of knowledge and ideas have enlightened my life. I deeply acknowledge his guidance and patience in my research, his incessant spirit and love for science inspires me each day. I extend my sincere gratitude for his invaluable support and advice in my career goals and for his endless moral support which has made me a stronger person. I would like to thank Dr. Stephan Patrick for supporting me in every way and being my advisor during my time away from University of Toledo. I would like to thank Dr. Robert Trumbly for his advice and help with the analysis of the microarray results and bioinformatics. I would like to thank Dr. Edwin Sanchez for his invaluable suggestions; his experience in the field of nuclear receptors has helped me immensely in developing my research projects. I would also like to thank Dr. Ivana de la Serna for her support and advice. I am thankful to all the past and present members of the lab, Marcela d’Alincourt Salazar, Mesfin Gonit, Suneethi Sivakumaran, Venkatesh Chari, Lily Huang, Thomas McFall, Rayna Rosati and Shoya Yamada for their encouragement and camaraderie. A special thanks to Marcela d’Alincourt Salazar for teaching me everything in the lab and for her advice and friendship. I am thoroughly indebted to Lily Huang for helping me with my vii experiments in the last few months; my dissertation would not be complete without her assistance. I thank all the faculty and students of the Department of Biochemistry and Cancer Biology at University of Toledo for their support and a friendly work environment. I would especially like to acknowledge the efforts of Jenifer Zak in supporting me during my time away from Toledo. I would also like to thank the members of the labs on the eighth floor of Karmanos Cancer Institute for supporting me during my transition to Detroit. I am grateful to Dr. Cecilia Speyer for her advice in troubleshooting my experiments. I would like to extend my sincere gratitude to Dr. Larry Matherly for his support and involving me in the Wayne State University Cancer Biology program activities. I would also like to thank Amanda Cook and Jean Guerin for their assistance with everything. I feel blessed to have my wonderful family and bow to my parents’ for their efforts in encouraging and supporting me. I would like to express my gratitude to my cousin, Snehal Kharkar and to my boyfriend, Gopal Iyer for their love and moral support. Lastly, I would like to thank all of my friends for their constant encouragement and appreciation. A special thanks to my roommates Akshada Sawant and Gurpanna Saggu for making my time in Toledo memorable. I would like to thank Thomas McFall and Rayna Rosati for bringing joy to my life in Detroit. viii Table of Contents Abstract.............................................................................................................................. iii Acknowledgments.……………………………………………………………………... vii Table of contents...………………….……………………………….……………..……. ix List of tables………………………………………………………………………...…… xi List of figures…………………………………………………………………........…… xii 1 – Literature Review.............…………………………………………………………..... 1 1.1 Breast cancer epidemiology, etiology and biologic subtypes................................... 1 1.2 Estrogen biology....................................................................................................... 5 1.3 Adjuvant therapy in estrogen receptor positive breast cancer.................................. 8 1.4 Tamoxifen Endocrine therapy................................................................................ 13 1.5 Mechanisms of resistance to tamoxifen.................................................................. 16 1.6 Estrogen receptor structure and mechanism of action............................................ 19 1.7 Gene repression by estrogen and de-repression by tamoxifen............................... 25 1.8 Carcinoma of lung, epidemiology and etiology...................................................... 28 1.9 Classification and management of lung cancer...................................................... 29 1.10 Pemetrexed in the treatment of NSCLC – single agent and combination therapy.................................................................................................................. 33 1.11 Mechanism of action of pemetrexed..................................................................... 36 1.12 Mechanisms of resistance to pemetrexed............................................................. 38 ix 1.13 Therapeutic applications of glucocorticoids......................................................... 40 1.14 Mechanism of action of the glucocorticoid receptor............................................ 42 1.15 Mechanisms of resistance to glucocorticoids......................................................
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