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 The Epithelial To Mesenchymal Transition In Breast Cancer Induces Alterations In Metabolism Esmeralda Ramirez-Peña Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Ramirez-Peña, Esmeralda, "The Epithelial To Mesenchymal Transition In Breast Cancer Induces Alterations In Metabolism" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 859. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/859 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]. THE EPITHELIAL TO MESENCHYMAL TRANSITION IN BREAST CANCER INDUCES ALTERATIONS IN METABOLISM By Esmeralda Quetzalcitlali Ramirez-Peña, B.S. APPROVED: ______________________________ Sendurai A. Mani, Ph.D. Advisory Professor ______________________________ Richard Behringer, Ph.D. ______________________________ Mikhail Kolonin, Ph.D. ______________________________ Suzanne Fuqua, Ph.D. ______________________________ Arun Sreekumar, Ph.D. APPROVED: ______________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences i THE EPITHELIAL TO MESENCHYMAL TRANSITION IN BREAST CANCER INDUCES ALTERATIONS IN METABOLISM A DISSERTATION Presented to the faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences In Partial Fulfillment For the Degree of DOCTOR OF PHILOSOPHY by Esmeralda Quetzalcitlali Ramirez-Peña, B.S. Houston, Texas May, 2018 ii Dedication To my parents and brother for the American dream that we embarked on together Para mis padres y hermano por el sueño Americano en que navegamos juntos iii Acknowledgements My dream of becoming a scientist was fulfilled with the support of many individuals and organizations that provided me with professional, educational, and emotional support. First, I would like to thank my parents, Mrs. Esperanza Peña-Rosales and Mr. Arturo Ramirez-Cuellar, for buying me my first microscope when I was six years old. Their sacrifices and perpetual support have allowed me to have the freedom to transform my education into the career of my dreams and encouraged me to fly as high as my heart desired. I would like to thank my brother, Arturo Ramirez-Peña, whose strength and positivity has always filled me with joy and laughter. I am thankful for the lessons I have learned from my family, particularly to be fearless, humble, and hard working in pursuit of great goals. I am eternally grateful to the MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences for nurturing me in an environment that is dedicated to students’ success. The faculty and staff went above and beyond their job descriptions; they listened to my concerns, encouraged my curiosity, gave me the freedom to practice leadership and community service, and always made me feel welcome. I would like to thank my mentor, Dr. Sendurai A. Mani for giving me the opportunity to develop my projects with my own creative freedom, for opening the door to many collaborations while challenging me to improve my scientific skills to the best of my potential. I will always remember our first conversation where he told me that the most important quality a scientist should have is passion. In his lab, I was blessed to meet wonderful colleagues and I cherish all those times where we engaged in scientific discussions that challenged and motivated me. I want to thank my “lab sisters” and current members of the Mani lab, Dr. Rama Soundararajan, Dr. Petra Den Hollander, Dr. Robiya Joseph, Neeraja Bhangre, Dr. Sridevi Addanki, and Mr. Paul Allegakoen. They showed me that hard work can be accomplished in a supportive and positive environment. Working by their side has been one of the best experiences in my career. iv I would also like to acknowledge previous members of the Mani lab who mentored me and taught me many skills; Dr. Joe Taube, Dr. Tapasree Roy Sarkar, Dr. Anurag Paranjape, Dr. Steve Werden, Dr. Mika Pietilä and Dr. Nathalie Sphyris. I would like to thank Dr. Geraldine Raja, Dr. Rebeca Romero-Aburto, Dr. Andria Schibler, and Dr. Patty Dimarco-Hewitt for their friendship and companionship in our journey together as graduate students. I would like to thank Ms. Vinita Shivakumar for sticking by my side for two years. She invigorated me with her curiosity and enthusiasm and mentoring her inspired me to strive to be a better teacher. I would like to thank our administrative support from the Translational Molecular Pathology (TMP) Department, Ms. Teresa Self, Ms. Barbara Sadeghi and Ms. Andrea Jones who always helped our lab run smoothly, and Dr. Celia Garcia-Prieto and Ms. Gabriela Mendoza for their assistance with my animal protocols. I am very grateful for the support of the TMP department led by Dr. Ignacio Wistuba whose dedication to trainee career development initiatives funded me with a travel award that gave me the opportunity to present my work at an international Keystone Conference. I would like to thank the leadership and of the TMP Interdisciplinary Translational Education and Research Training Program (iTERT), Dr. Ignacio Wistuba, Dr. Rama Soundararajan, Dr. Ann Killary, and administrative support Ms. Sarah Fayle and Mr. Bert Shaw I benefited immensely from the iTERT journal club, technical workshops, and seminar series and they always listened to my ideas with enthusiasm. My project and progress was overseen by mentors who provided me with constructive suggestions and were dedicated to my success. I would like to thank the members of my advisory committee, Dr. Richard Behringer, Dr. Mikhail Kolonin, Dr. Suzanne Fuqua, and Dr. Arun Sreekumar, for taking the time to listen to my concerns and making sure that I remained on the correct path. I would also like to thank my mentors from the Genes and Development graduate program: Dr. Swathi Arur, Dr. Michael Galko, Dr. Andrew Gladden, Dr. Russell Broaddus, Dr. Jichao Chen, Dr. Sadhan Majumder, Dr. William Mattox, and Dr. Pierre McCrea and the G&D program manager Ms. Elisabeth Lindheim who always helped me with a caring attitude. v The development of my projects would not have been possible without the support of our collaborators and those who generously shared their expertise, instruments, and reagents with us in the spirit of team science. I would like to thank members of Dr. Sreekumar’s lab, Dr. James Arnold and Dr. Salil Bhowmik, for their patience and dedication to our EMS project that led to many future projects. Also, Dr. Serena Chan from Biolog, Dr. Arnold Levine and members of his lab for our insightful discussions during our joint lab meetings, Dr. Jeffrey Rosen and members of the Baylor Breast Center for giving me the opportunity to share my work, Dr. Elsa Flores, Dr. Avinash Venkatanarayan, Dr. Michael Davies, members of Dr. Davies’ lab, Dr. Vashisht Yennu- Nanda, Rishika Prasad, and Grant Fisher, Dr. Peng Huang, Dr. Helen Pelicano, Dr. Lynn Zechiedrich, and Zach Conley were all extremely instrumental in guiding me with their knowledge of cancer metabolism and sharing their instruments for the metabolic assays in this thesis. I am extremely grateful to Dr. Li Ma and Dr. Kenneth Scott for providing us with vectors for this study, and Dr. José Matés and Dr. Javier Márquez from the University of Malaga in Spain for providing us with the GLS and GLS2 antibody. I want to acknowledge the Association of Minority Biomedical Researchers (AMBR) and its leadership Dr. Marenda Wilson-Pham and Dr. Andy Bean for giving me the opportunity to exercise leadership and making me aware that my role as a minority in science is extremely valuable. I also want to thank Dr. Sina Safayi for believing in me and providing me with the tools that opened the doors to the future of my dreams. I also thank Dr. Thomas Goka, whose kind and reassuring words still resonate with me. Last but not least, I want to thank my other Houston family who encouraged me and were a source of much happiness. I want to thank Dr. Marco Farina for sharing this journey with me and always reminding me that this sacrifice will be fruitful one day. I also want to thank my dear friends who never stopped cheering me on, understood all the times that I went “missing” because I was either too busy or too tired, and I could always count on to be ready to enjoy life with me. vi THE EPITHELIAL TO MESENCHYMAL TRANSITION IN BREAST CANCER INDUCES ALTERATIONS IN METABOLISM Esmeralda Quetzalcitlali Ramirez-Peña, B.S. Supervisory Professor: Sendurai A. Mani, Ph.D. Metastasis is currently incurable. Recent studies suggest that metabolic reprogramming significantly impacts metastatic progression. Understanding the underlying biology of how metabolic reprogramming influences metastasis will shed light on developing novel ways to treat metastasis and is of urgent clinical need. A potent mediator of metastatic potential in breast cancer is the winged helix/Forkhead domain transcription factor FOXC2. We have previously shown that FOXC2 is necessary and sufficient to promote metastasis through induction of the epithelial to mesenchymal transition (EMT). EMT is a latent embryonic program that is aberrantly induced in breast cancer cells conferring migratory and invasive capabilities in addition to cancer stem cell (CSC) properties.