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Anti-Cancer Mechanism of Trastuzumab Via Blocking Nuclear HER2 Function and Epigenetic Mechanism of Resistance

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Anti-Cancer Mechanism of Trastuzumab Via Blocking Nuclear HER2 Function and Epigenetic Mechanism of Resistance Anti-Cancer Mechanism of Trastuzumab via Blocking Nuclear HER2 Function and Epigenetic Mechanism of Resistance by Babak Nami Mollalou A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Medical Sciences – Medical Genetics University of Alberta © Babak Nami Mollalou, 2020 ABSTRACT HER2 receptor tyrosine kinase (encoded by ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (known as HER2-positive breast cancers). Overexpression of HER2 causes overactivation of downstream receptor tyrosine kinase pathways including PI3K/Akt and MAPK pathways and is a poor prognosis factor in breast cancer. Trastuzumab which is a humanized monoclonal antibody designed to target HER2 receptor is approved by FDA to treat patients with early-stage and metastatic HER2-positive breast cancer as an adjuvant in combination with other chemotherapy. However, approximately 60-70% of HER2-positive breast cancer patients develop de novo resistance to trastuzumab, partially due to the loss of HER2 expression on their tumor cells during the treatment. Little is known about the exact mode of action of trastuzumab in inhibiting HER2-positive breast cancer cells and the mechanism of trastuzumab resistance. The overall aim of this thesis was to study the mechanism of action of trastuzumab in inhibiting HER2-positive breast cancer and the mechanism of resistance to trastuzumab. We found that HER2 overexpression in Chinese hamster ovary (CHO) cells had no major effect on the activation of downstream PI3K/Akt and MAPK pathways, however, significantly increased the cell growth. These suggest a non-canonical oncogenic function of HER2. Our results showed that trastuzumab blocks proteolytic cleavage of HER2, production and nuclear localization of a C-terminal truncated HER2 protein with an approximate molecular weight of 85 kDa (p85HER2). Trastuzumab showed a synergic effect with a proteinase inhibitor in blocking HER2 cleavage and production of p85HER2 that led to cell growth inhibition. This is a new molecular anti-cancer mechanism of trastuzumab. Immunoprecipitation of nuclear p85HER2 followed by mass spectrometry analysis showed that p85HER2 directly interacts with the spliceosome protein complex and transcription factors and mediates in RNA processing, splicing, and gene expression regulation. These results demonstrate that nuclear p85HER2 mediates in the regulation of RNA processing and gene expression. Gene set enrichment analysis of the mass spectrometry results also revealed that most of the nuclear p85HER2 client proteins are downstream targets for oncogenic/stemness transcription factors which are master regulators of breast cancer stemness and epithelial-mesenchymal transition (EMT). These results ii demonstrate a novel mechanism of action of trastuzumab in blocking a non-canonical pathway of HER2 via nuclear function of p85HER2. In this study, we also hypothesized that EMT abrogates HER2 expression by chromatin- based epigenetic silencing of ERBB2 gene as a mechanism of development of trastuzumab resistance. we found positive and negative correlation of HER2 expression levels with epithelial and mesenchymal phenotypes respectively. This indicates that epithelial-like cells are HER2- high, while mesenchymal-like cells are HER2-low. We found that the correlation is due to active and inactive chromatin dynamics of ERBB2 gene in epithelial-like and mesenchymal-like cells respectively. HER2-low mesenchymal-like breast cancer cell lines revealed less promoter- enhancer interaction and larger chromatin loops compared to the HER2-high epithelial-like breast cancer cell lines. Further, the cell line with higher expression levels of HER2 showed higher numbers of chromatin-chromatin interaction, super-enhancers and topologically associated domains (TADs) at the chromatin of ERBB2 gene and flanking regions. The lower HER2 expression, the higher EMT phenotype, and inactivated chromatin all were found correlated with a lower response to lapatinib. We also demonstrated that inducing EMT of HER2-positive cancer cells results in the downregulation of HER2 expression and lower binding rate of trastuzumab. These results show that the downregulation of HER2 expression in mesenchymal-like cells derived from HER2-positive breast cancer cell lines is due to ERBB2 gene silencing by global epigenetic reprogramming during EMT. We strongly suggest further studying the oncogenic function of p85HER2 through regulation of coding and non-coding RNA processing as well as transcription co-factor function of p85HER2 in breast cancers. We also suggest testing proteinase inhibitors in combination with trastuzumab and lapatinib to prevent the non-canonical pathways of HER2 and development of de novo trastuzumab resistance in HER2-positive breast cancers. We here strongly recommend developing and testing HER2-targeting small molecules inhibitors to inhibit HER2 cleavage as an alternative therapy for trastuzumab to use in combination with lapatinib. Further, we propose targeting EMT and cancer stem cells as an effective approach to inhibit tumor growth and overcome drug resistance in breast cancer. iii PREFACE This thesis is an original works carried out primarily by Babak Nami Mollalou under supervision and at the laboratory of Dr. Zhixiang Wang of the Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta. This thesis was supported in part by grants from the Canadian Breast Cancer Foundation (CBCF) to Zhixiang Wang, and Canadian Institutes of Health Research (CIHR) to Zhixiang Wang. Babak Nami Mollalou was supported by a graduate scholarship from Women and Children’s Health Research Institute (WCHRI). Chapter 1 contains some parts of two independent review articles published in the journal “Cancers” (2017 Apr 26;9(5), and 2018 Sep 20;10(10)). Chapter 3 contains original work carried out equally by Hamid Maadi and Babak Nami Molallou (co-first authors), published in the journal “BMC Cancer” (2018 Mar 1;18(1):238)) Chapter 4 contains original work carried out equally by Babak Nami Mollalou and Hamid Maadi (co-first authors), published in the journal “Cancers” (2019 Mar 16;11(3)). Chapter 5 contains unpublished original work carried out primarily by Babak Nami Mollalou. Chapter 6 contains unpublished original work carried out primarily by Babak Nami Mollalou. Chapter 7 contains some parts of two independent review articles published in the journal “Cancers” (2017 Apr 26;9(5), and 2018 Sep 20;10(10)). iv ACKNOWLEDGMENTS Firstly, I would like to express my special appreciation and thanks to my advisor Dr. Zhixiang Wang for the continuous support of my Ph.D. study and related research, for his patience, motivation, his reference letters and immense knowledge. The doors to his office was always open whenever I ran into a trouble spot or had a question about my research. His guidance helped me in all the time of research and writing of this thesis. I am very proud of studying under the supervision of Zhixiang. I could not have imagined having a better advisor and mentor for my Ph.D. study. I would also like to thank my co-supervisor and the chair of the Department of Medical Genetics Dr. Michael Walter and my other Ph.D. committee member Dr. Gordon Chan of the Department of Oncology for their insightful comments and encouragement, advice on research as well as on my career and providing reference letters for my applications patiently. But also for the hard question which incented me to widen my research from various perspectives. I am also thankful to Dr. Jean Zhao of Harvard University Dana-Farber Cancer Institute for traveling to Edmonton and serving as external examiner for my Ph.D. defence. I would also like to thank Dr. Sarah Hughes and Dr. Rachel Wevrick of the Department of Medical Genetics as graduate coordinators of my Ph.D. program for their supports and followIng up my study and research. I am especially grateful to Dr. Hughes who gave access to her laboratory and facilities. Without her precious support, it would not be possible to conduct this research. I am also thankful to Dr. David Eisenstat, the chair of the Department of Oncology for his hard course that pushed me forward to learning more and more about epigenetic regulation in cancer, and for his helps in provideing reference letters and discussing carrier oppurtunities. I thank my fellows and friends at Dr. Wang lab, our technician Xinmei Chan, postdoctoral fellow Junfeng Tong, students Hamid Maadi, Ping Wee, Daniel Brandwein, Abdalla Abdrabou and the rest of my friends at the Department of Medical Genetics for sharing the laboratory in the past 4 years. A special thank to Hamid Maadi, who worked with me in two mutual projects, for sharing results, his enthusiasm and the stimulating discussions. v I hereby express my gratitude to WCHRI, FGSR, and the Department of Medical Genetics at University of Alberta for the graduate shcolarships and awards, and to CBCF and AIHS for financially supporting my research. And finally, last but not least, I must express my very profound gratitude to my parents and sisters and to my wife Avrin for providing me with unfailing support and continuous encouragement throughout my years of study and through the process of researching and writing this thesis. I am also grateful to my cat pet Think for her love, the tones of positive energy, and for all the funny moments in our home. Avrin! thank you for sharing your knowledge and helping me in bioinformatics analysis of parts of my research.
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