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Epigenetic Mechanisms of Gene Regulation in Human Breast Cancer

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Epigenetic Mechanisms of Gene Regulation in Human Breast Cancer EPIGENETIC MECHANISMS OF GENE REGULATION IN HUMAN BREAST CANCER Ashley Garrett Rivenbark A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology. Chapel Hill 2007 Approved by: William B. Coleman, Ph.D. Channing J. Der, Ph.D. William K. Funkhouser, M.D., Ph.D. Wendell D. Jones, Ph.D. William K. Kaufmann, Ph.D. © 2007 Ashley Garrett Rivenbark ALL RIGHTS RESERVED ii ABSTRACT Ashley Garrett Rivenbark: Epigenetic Mechanisms of Gene Regulation in Human Breast Cancer (Under the direction of William B. Coleman, Ph.D.) Breast cancer represents a significant health problem and improvements in our ability to prevent, diagnose, and treat the disease requires a greater understanding of the molecular basis of breast carcinogenesis. Epigenetic mechanisms play a major role in breast carcinogenesis, with DNA methylation accounting for most epigenetic gene silencing, affecting a number of different gene targets. However, mechanisms of DNA methylation- dependent silencing are poorly understood. To identify epigenetically-regulated genes in breast cancer, MCF-7 breast cancer cells were exposed to demethylating treatment and gene expression patterns were examined by microarray analysis. Genes with increased expression after demethylation treatment that returned to control levels after treatment withdrawal were directly assessed for DNA methylation by bisulfite sequencing. A group of 20 putative methylation-sensitive genes were identified that could be classified into three groups based upon their promoter CpG features. The majority of these methylation-sensitive genes lacked a conventional DNA methylation target (CpG island), resulting in an expanded model for epigenetic regulation of gene expression that recognizes the importance of all promoter CpGs. The breast tumor suppressor gene CST6 (Cystatin M) is epigenetically silenced in MCF-7 breast cancer cells. CST6 is subject to methylation-dependent regulation in multiple breast cancer cell lines, primary breast tumors, and lymph node metastases, and gene expression status correlates with promoter hypermethylation. These results suggest that iii methylation dependent gene silencing of CST6 represents an important mechanism for loss of CST6 during breast carcinogenesis. The mechanisms that control CpG island methylation are poorly understood. CST6 was utilized as an index gene for the identification of cis elements that direct promoter CpG methylation. The methylation-sensitive CST6 promoter was assembled into luciferase reporter constructs and transfected into model breast cancer cell lines that methylate or do not methylate the CST6 promoter. Truncation of the CST6 promoter disassociated a putative instructional cis regulatory sequence located in the 5’ upstream promoter region of CST6 that functions to direct CpG methylation. The observations and results described in this dissertation significantly advance our understanding of methylation-sensitive genes and mechanisms governing DNA methylation in breast carcinogenesis. iv ACKNOWLEDGMENTS First and foremost I would like to thank my advisor Bill Coleman, for his guidance, wisdom, support, and encouragement. He has enriched my experience in graduate school by allowing me to help him with many endeavors, including writing grants, reviews, and manuscript commentaries. My achievements and success in graduate school are mostly due to his mentorship and support. I will forever be grateful to him. Thank you to all the people in my lab who have made coming to work exciting, always interesting, and mostly enjoyable. I want to give special thanks to Devon, who has been my ‘little sister’ in the lab. Teaching and learning from her has been a joy. I would like to express my gratitude to my dissertation committee members, Channing J. Der, William K. Funkhouser, Wendell D. Jones, and William K. Kaufmann. I appreciate all of their time, effort, support, and encouragement. I want to especially thank Wendell for all of his microarray analysis and statistical help. I want to give special thanks to my parents, who have taught me to live my life according to God’s will, and have encouraged and supported me throughout all endeavors. Thank you for your prayers. I love you both so much. Thank you to my brother, Justin, for supporting me in graduate school, always keeping things in perspective, and making me laugh in all situations. I want to thank Patsy, Dannie, and Ginnie for their enthusiasm and support throughout the years I have known them. Thanks to my friends who have been my support system and prayer warriors throughout graduate school (and most of my life), Stephanie, Megan, and especially Laura. Thank you Laura for being so understanding, encouraging, v enthusiastic, and someone I can count on for anything. I am so blessed to have you as a friend! Most importantly, thank you to my husband and best friend, Jason, for your unconditional love, support, wisdom, advice, and uncanny ability to understand lab situations. I truly appreciate all you have done for me. I love you. vi TABLE OF CONTENTS LIST OF TABLES...............................................................................................................xii LIST OF FIGURES ............................................................................................................xiii LIST OF ABBREVIATIONS..............................................................................................xv I. INTRODUCTION.............................................................................................................1 A. Breast Cancer ................................................................................................................1 Breast Cancer Epidemiology ........................................................................................1 Natural History of Breast Cancer..................................................................................2 B. Molecular Pathogenesis of Breast Cancer.....................................................................5 Breast Cancer Susceptibility Genes..............................................................................6 Environmental and Epigenetic Factors of Breast Cancer Susceptibility.................................................................................................................7 C. Mechanisms of Epigenetic Regulation in Carcinogenesis ............................................7 DNA Methylation in Cancer.........................................................................................8 DNA Methylation in Human Breast Cancer.................................................................8 Targets of DNA Methylation......................................................................................12 Mechanisms of Regulation of DNA Methylation.......................................................15 D. Cystatins and Cancer: Methylation-sensitive Genes that Contribute to Breast Tumorigenesis and Progression ................................................19 Cysteine Protease Inhibitors - Cystatins .....................................................................19 Cystatin Super-Family ................................................................................................19 CST6 (Cystatin M): A Prototype Methylation-sensitive Gene ..................................20 vii E. Summary and Significance..........................................................................................22 II. EXPERIMENTAL PROCEDURES ..............................................................................24 A. Breast Cancer Cell Line Culture .................................................................................24 B. Treatment of Human Breast Cancer Cells with Demethylating Agents.........................................................................................................................25 MCF-7 Breast Cancer Cells Treated with 5-aza-2’- deoxycytidine and Trichostatin A...............................................................................25 Hs578T, MDA-MB-435S, MDA-MB-436, MDA-MB-453, MCF-7, and ZR-75-1 Breast Cancer Cells Treated with 5-aza- 2’-deoxycytidine .........................................................................................................26 C. Human Breast and Lymph Node Tissues....................................................................26 D. RNA Isolation from Human Breast Cancer Cell Lines...............................................27 E. Affymetrix Microarray Analysis of Gene Expression.................................................27 F. Semiquantitative RT-PCR Analysis of Gene Expression............................................32 G. Quantitative Real-Time PCR ......................................................................................32 H. Promoter and 5’-Upstream Sequence Analysis of Putative Methylation-sensitive Genes ......................................................................................34 I. Construction of Reporter Gene Constructs...................................................................35 CST6 Gene Promoter Constructs ................................................................................35 In Vitro CST6 Promoter Construct Methylation.........................................................39 J. Luciferase Reporter Assay ...........................................................................................39
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