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TRIM24 As an Oncogene in the Mammary Gland

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TRIM24 As an Oncogene in the Mammary Gland The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2018 TRIM24 as an Oncogene in the Mammary Gland Aundrietta Duncan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Cancer Biology Commons, Medicine and Health Sciences Commons, and the Other Genetics and Genomics Commons Recommended Citation Duncan, Aundrietta, "TRIM24 as an Oncogene in the Mammary Gland" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 845. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/845 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TRIM24 AS AN ONCOGENE IN THE MAMMARY GLAND by Aundrietta DeVan Duncan, M.S. APPROVED: ______________________________ Michelle C. Barton, Ph.D. Advisory Professor ______________________________ Richard Behringer, Ph.D. ______________________________ Guillermina Lozano, Ph.D. ______________________________ Sendurai Mani, Ph.D. ______________________________ Jeffrey T. Chang, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences TRIM24 AS AN ONCOGENE IN THE MAMMARY GLAND A Dissertation Presented to the Faculty of The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences in Partial Fulfillment Of the Requirements for the Degree of Doctor of Philosophy By Aundrietta DeVan Duncan, MS Houston, Texas May 2018 ii For Cohen. iii Acknowledgements To my mentor, Dr. Michelle C. Barton. For seeing in me what I did not see in myself, being patient beyond words, always finding the silver lining, and giving me the freedom to explore my passions, I am eternally grateful. You are a brilliant example of what living in one’s purpose means. To my committee members past and present - Dr. Guillermina Lozano, Dr. Sendurai Mani, Dr. Jeff Chang, Dr. Elsa Flores, Dr. Roel Verhaak, Dr. Hui-Kuan Lin, Dr. Jill Schumacher, Dr. Xiobing Shi, Dr. Russel Broaddus, Dr. Mark Bedford – for supporting me, challenging me, not always telling me what I wanted to hear, encouraging me, and filling in when I needed. To Dr. Richard Behringer for every interaction that led to P!NK. To the Barton lab members, past and present – Dr. Joe Taube, Dr. Wen-Wei Tsai, Dr. Svitlana Kurrina, Dr. Teresa Yiu, Dr. Ryan McCarthy, Dr. Srikanth Appikonda, Dr. Kaushik Thakkar, Dr. Jing Li, Sabrina Stratton, Kendra Allton, Dr. Abhinav Jain, Dr. Thushangi Parthiraja, Dr. Lalit Patel, Dr. Kadir Akdemir. You each have contributed to my growth as a scientist and a person in your own unique way. Dr. Shiming Jiang, Hui Wei without whom this project would not be possible. To all of the GSBS staff for making our school a welcoming environment and all of the hard work you do to keep everything running. To my student organization colleagues – Jill Losh, Alex Perakis, Erin Atkinson, and many others - your passion for service and making GSBS a place where all students feel welcome inspires me. iv To the Behringer lab members especially Dr. Rachel Mullen and Jenny Deng. You all were my second lab and your continued friendship means more to me than you know. To my collaborators Dr. Jan Parker-Thornburg, Dr. Stacey Moulder, Dr. Jeff Chang, Dr. Michael Gagea, Dr. Michael Gilcrease, Nancy Otto for elevating the possibilities of the project and making real the possible implications beyond the bench. To my supporters the strong and lovely women of the American Legion Auxiliary, the Tzu Chi Organization, the family of R.W. Butcher, and the National Institutes of Health Ruth L. Kirchtein fellowship program. To the Genes and Development program faculty, staff, and students for being a community in which I felt comfortable to be myself. To those who fit in one of the above categories and have become dear friends, Cheryl Spitzenberger, Elisabeth Lindhiem, Susan Simon, Dr. Lindsey Minter, Dr. Zeynep Coban Akdemir. Having gained your friendship during this journey is one of my most meaningful accomplishments. To my family Paula, William, Joyce, Kevin, and Cherrelle Duncan. For being my inspiration, my role models, my disciplinarians, prayer warriors, confidants, my biggest fans. Anything I accomplish in life is because of you. To my husband, Christopher Broussard, for being my balance. v To Cohen - you have been my motivation even before you came into existence. vi Abstract TRIM24 AS AN ONCOGENE IN THE MAMMARY GLAND Aundrietta DeVan Duncan, M.S. Advisory Professor: Michelle C. Barton Despite the many advances made in breast cancer research and treatments, breast cancer remains one of the deadliest diseases plaguing women worldwide. While many findings on genetic mutations and their role in predisposing people to breast cancer have been uncovered, we are just beginning to understand the extent to which epigenetic regulators promote tumorigenic phenotypes, metastasis, and chemotherapeutic resistance. Moreover, new experimental tools offer the ability to address questions we were previously unable to assess. My project takes advantage of a new mouse model to understand the role of a proto-oncogenic, transcriptional co- regulator, TRIM24, in mammary gland development and disease. We previously reported an unknown binding partner and negative regulator of p53, Tripartite Motif protein 24 (TRIM24). TRIM24 is a multifunctional protein, which acts as a co- regulator of estrogen receptor, a histone reader with tandem PHD and Bromo domains, and a ubiquitin E3-ligase targeting p53 by its RING domain. TRIM24 is over-expressed in human breast cancers, which is correlated with poor patient survival. Previous in cellulo studies in our lab show that TRIM24 over-expression leads to transformation of immortalized human mammary epithelial cells. However, whether over-expression of TRIM24 drives cancer development in vivo remains unknown. To address this gap in our knowledge, we developed a physiologically relevant mouse model to determine if over-expression of TRIM24 promotes tumor development in mammary vii epithelial cells, consistent with TRIM24 function as an oncogene. We hypothesize that TRIM24 acts as an oncogene in the mammary gland. To test this hypothesis, we generated transgenic mice, which in the presence of cre- recombinase, conditionally over-express mouse TRIM24 fused to a C-terminal FLAG epitope tag. Our studies reveal that increased expression of Trim24 in the mouse mammary gland is sufficient to drive tumorigenesis by 8 months of age. To facilitate genome wide and targeted therapeutic studies, I developed multiple primary cell lines (tumor and normal mammary epithelia) from each genotype. Colony formation and proliferation assays indicate that over-expression of TRIM24 gives cells a survival and proliferative advantage. RNA-deep sequencing and genome-wide binding profiles of these tumor-derived cell lines reveal that TRIM24 over-expression may be a direct driver of the epithelial-mesenchymal transition (EMT). These data corroborate unpublished in cellulo data from our lab, which implicate TRIM24 as a metastasis-promoting protein through its ability to activate EMT gene expression. Furthermore, we have observed an over-representation of metaplastic breast carcinomas (MpBC), a rare and devastatingly aggressive disease that has an EMT signature, in profiles of tumors generated in our mouse model. We have performed exome- sequencing, RNA-sequencing and immunohistochemistry on mice, which are currently being compared to human MpBC patient samples with the end goal of identifying the common alterations and substantiate TRIM24 as a player in the development of the MpBC phenotype. Finally, we present our mouse model as a useful tool to test the efficacy of potential therapeutics targeting MpBC and other breast cancers. viii ACKNOWLEDGEMENTS ................................................................................................................ IV ABSTRACT ................................................................................................................................. VII LIST OF FIGURES ......................................................................................................................... XI LIST OF APPENDICES .................................................................................................................. XII CHAPTER 1: INTRODUCTION .........................................................................................................1 1.1 COMPARATIVE ANATOMY OF THE MAMMARY GLAND ........................................................................... 2 1.2 TRANSCRIPTIONAL REGULATION IN THE DEVELOPING MAMMARY GLAND ................................................ 5 1.3 PATHOLOGIES OF THE BREAST WITH A FOCUS ON METAPLASTIC BREAST CANCERS ....................................... 9 1. 4 TRIM24
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