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Implications of Breastfeeding in Triple Negative Breast Cancer THESIS

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Implications of Breastfeeding in Triple Negative Breast Cancer THESIS Implications of Breastfeeding in Triple Negative Breast Cancer THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Mustafa M. Basree Graduate Program in Anatomy The Ohio State University 2017 Thesis Committee: Bhuvaneswari Ramaswamy, MD MRCP, Research Advisor Gustavo Leone, PhD, Research Advisor Eileen Kalmar, PhD, Academic Advisor Sarmila Majumder, PhD Kirk McHugh, PhD Copyright by Mustafa M. Basree 2017 Abstract Due to high mortality associated with triple negative breast cancer (TNBC), a prevention program has the potential to protect many women against this disease. Recent epidemiological and meta-analysis studies revealed a possible correlation between a lack of breastfeeding and development of TNBC. African-American (AA) women have a disproportionate burden of developing aggressive TNBC, a sub-population with higher parity rates and lower prevalence of breastfeeding. The reasons for why parity and breastfeeding affect breast cancer risk are unclear, but recent studies revealed that the pregnancy-lactation cycle (which leads to remodeling of the mammary glands) alters breast morphology and microenvironment, thereby modifying breast cancer risk. Natural weaning (NW), the gradual cessation of breastfeeding, results in a measured reduction of the ductal structures, termed involution. Conversely, the decision not to breastfeed results in a hastened involution, or abrupt involution (AW). We modeled NW and AW in wild- type mice by restricting breastfeeding to 28 and 7 days respectively. Striking differences in the distribution of cell populations were observed in the mammary glands of AW mice compared to NW mice. Fluorescence activated cell sorting analysis revealed an expansion of the luminal progenitor cells with a concomitant decrease in mammary stem- cell enriched/basal compartment in the glands of the AW cohort. This observation is reminiscent of previous observations in TNBC in both animal models and human pre- ii neoplastic BRCA1-mutation carrier patients. The AW mammary epithelium is more proliferative, inflammatory, exhibit increased estrogen receptor expression, and is immune active 56 days postpartum. Moreover, we observed more collagen deposition in the AW glands compared with NW, which has been correlated with reduced risk for TNBC. These observations highlight a key difference between the lactating and non- lactating mammary glands at the molecular level that could predispose the AW glands to tumorigenesis. We hope our findings will one day persuade more women to choose breastfeeding as a measure to help prevent TNBC. iii Dedication This document is dedicated to my family and breast cancer patients. iv Acknowledgments Attempting to satisfy my inquisitive and curious self, I reached out to Dr. Bhuvaneswari Ramaswamy, MD, MRCP shortly after I was admitted to the anatomy graduate program to join her team knowing that her research interests resonate well with those of mine. Almost two years, a-lot-coffee and weekends, later I’m happy to contribute to the scientific community with preliminary answers to a question of great public health interest on the topic of breastfeeding and development of breast cancer. I would like to extend my sincere gratitude to Dr. Ramaswamy, a caring and daring physician-scientist, for mentoring and believing in me throughout my graduate studies. I would also like to thank Dr. Gustavo Leone, PhD who was instrumental in providing guidance and framework for which I could carry out my thesis work. Dr. Sarmila Majumder, for whom the day-to-day questions were directed and experimental glitches were resolved, were kind with her time and patient with me. Anthony Trimboli, PhD, Christopher Koivisto, DVM and Cecilia Cuitino, DVM, PhD were helpful in providing inputs regarding mouse biology and genetics. Many thanks to the Solid Tumor Program Histology Core for processing formalin-fixed sections. Sincere thanks to Gina Sizemore, PhD for sharp critique and FACS expertise. Thanks to Anisha Hammer whose suggestions regarding collagen and mammary gland biology were invaluable. The Anatomy Department was incredibly accommodating of my lab schedule and supportive of my professional v endeavors as rare scheduling conflicts emerged with my teaching appointment. Thank you, Dr. Kirk McHugh, PhD and Dr. Eileen Kalmar, PhD for serving as committee members for this project, it is greatly appreciated. Lastly, I would like to thank my friends and family for their unwavering support. They say best things in life are unexpected. Joining Dr. Leone’s lab and Ramaswamy’s team has been a wonderful milestone in my life. vi Vita August 4, 1989 ...............................................Born – Baghdad, Iraq Education 2013................................................................B.S. Biology, The Ohio State University 2010 ...............................................................CERT. Biomedical and Laboratory Sciences, Boston University Professional Experience 2016-present ..................................................Graduate Teaching Associate, College of Medicine, Division of Anatomy, The Ohio State University 2015-present ..................................................Graduate Research Assistant, Department of Internal Medicine, Division of Medical Oncology, The Ohio State University 2014-2015 .....................................................Clinical Research Coordinator, Aventiv Research, Columbus OH 2012-2013 .....................................................Undergraduate Research Assistant, Department of Pathology, The Ohio State University vii 2011 ...............................................................Research Coordinator, Department of Pediatric Neurology, Rush University Medical Center 2009-2010 .....................................................Associate Scientist I, EMD Serono INC viii Publications 1. Helong Zhao, Tasha Wilkie, Yadwinder Deol, Amita Sneh, Akaansha Ganju, Mustafa Basree, Mohd W Nasser and Ramesh K Ganju. “miR-29b defines the pro-/anti- proliferative effects of S100A7 in breast cancer”. Molecular Cancer 2015, 14:11. Abstracts and Posters 1. Basree, Mustafa M., Sarmila Majumder, PhD, Bhuvaneswari Ramaswamy, MD, MRCP, Gustavo Leone, PhD. “Potential benefit of prolonged breastfeeding against triple negative breast cancer by reducing luminal progenitor cells in the mammary epithelium”. Presented at The Ohio State University Wexner Medical Center Research Trainee Day in Columbus, OH. April 2017. 2. Basree, Mustafa M., Janani Ravi, Amita Sneh PhD., Mohd Nasser, PhD., Ramesh Ganju, PhD. “Role of synthetic cannabinoid agonist JWH-015 in regulation of CXCL12-CXCR4 signaling in non-small cell lung cancer”. Presented at The Ohio State University Denman Undergraduate Research Forum in Columbus, OH. March 2013. ix 3. Basree, Mustafa M., Helong Zhao, Mohd Nasser, PhD., Ramesh Ganju, PhD. “miR-29b inhibits tumor growth and metastasis by modulating S100A7/Psoriasin gene expression in MCF-7 breast cancer cells”. Presented at the 7th Annual Fall Undergraduate Research Week & Student Poster Forum in Columbus, OH. September 2013. x Fields of Study Major Field: Anatomy xi Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita .................................................................................................................................... vii List of Figures ................................................................................................................... xv List of Tables .................................................................................................................. xvii Abbreviations ................................................................................................................. xviii Chapter 1: Introduction to the Mammary Gland................................................................ 1 1.1: Introduction to the Mammary Gland ............................................... 1 1.1.1: Embryology of the Mammary Gland .................................. 1 1.1.2: Structure of the Mammary Gland ........................................ 3 1.1.3: Epithelial Cell Hierarchy ..................................................... 5 1.1.4: Pregnancy, Lactation, and Gland Remodeling .................... 6 1.1.5: Mammary Gland Involution ................................................ 7 1.2: Introduction to Breast Cancer ......................................................... 9 1.2.1: Breast Cancer ...................................................................... 9 1.2.2: Breast Cancer Classification ............................................. 11 1.2.3: Triple Negative Breast Cancer .......................................... 12 1.2.4: Parity, Breastfeeding, and TNBC ...................................... 14 1.3: Chapter 1 Figures .......................................................................... 18 1.4: Chapter 1 Tables ............................................................................ 30 Chapter 2: Material and Methods ..................................................................................... 32 2.1: Animals ........................................................................................
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