RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes

University of Massachusetts Medical School <a href="/goto?url=https://escholarship.umassmed.edu/" target="_blank">eScholarship@UMMS </a><a href="/goto?url=https://escholarship.umassmed.edu/gsbs_diss" target="_blank">GSBS Dissertations and Theses </a>2017-12-12 <a href="/goto?url=https://escholarship.umassmed.edu/gsbs" target="_blank">Graduate School of Biomedical Sciences </a>RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes Deli Hong University of Massachusetts Medical School <a href="/goto?url=https://arcsapps.umassmed.edu/redcap/surveys/?s=XWRHNF9EJE" target="_blank">Let us know how access to this document beneﬁts you. </a>Follow this and additional works at: <a href="/goto?url=https://escholarship.umassmed.edu/gsbs_diss?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">https:</a><a href="/goto?url=https://escholarship.umassmed.edu/gsbs_diss?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">/</a><a href="/goto?url=https://escholarship.umassmed.edu/gsbs_diss?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">/</a><a href="/goto?url=https://escholarship.umassmed.edu/gsbs_diss?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">escholarship.umassmed.edu/gsbs_diss </a> Part of the <a href="/goto?url=http://network.bepress.com/hgg/discipline/12?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">Cancer Biology Commons</a>, and the <a href="/goto?url=http://network.bepress.com/hgg/discipline/10?utm_source=escholarship.umassmed.edu%2Fgsbs_diss%2F949&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">Cell Biology Commons </a>Repository Citation Hong D. (2017). RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes. GSBS Dissertations and Theses. <a href="/goto?url=https://doi.org/10.13028/M21Q2F" target="_blank">https:</a><a href="/goto?url=https://doi.org/10.13028/M21Q2F" target="_blank">/</a><a href="/goto?url=https://doi.org/10.13028/M21Q2F" target="_blank">/</a><a href="/goto?url=https://doi.org/10.13028/M21Q2F" target="_blank">doi.org/10.13028/M21Q2F</a>. 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For more information, please contact <a href="mailto:[email protected]" target="_blank">[email protected]</a>. RUNX1 CONTROL OF MAMMARY EPITHELIAL AND BREAST CANCER CELL PHENOTYPES A Dissertation Presented By Deli Hong Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 12, 2017 Program of Cell Biology RUNX1 CONTROL OF MAMMARY EPITHELIAL AND BREAST CANCER CELL PHENOTYPES A Dissertation Presented By Deli Hong This work was undertaken in the Graduate School of Biomedical Sciences Program of Cell Biology The signature of the Thesis Advisor signifies validation of Dissertation content Gary S. Stein, Ph. D., Thesis Advisor The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation Leslie Shaw, Ph. D., Member of Committee Kendall Knight, Ph. D., Member of Committee Jeffery Nickerson, Ph. D., Member of Committee Robert Weinberg, Ph. D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee Hong Zhang, Ph.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the School. Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences December 12, 2017 Acknowledgements Foremost, I would like to express my deepest gratitude to my thesis advisor Prof. Gary Stein, Dr. Jane Lian and Dr. Janet Stein for their continuous guidance and generous support throughout my doctoral study, without which this experience would not have been the positive experience it was. They always support me to pursue my own scientific interests in the lab. This great experience working in their lab helped me to mature into a well-rounded scientist. I would like to give thanks to Jason Dobson for his guidance during the initial stage of my doctoral study doctoral study. Specific thanks go to Dr. Andrew Fritz, who is my primary collaborator in the lab. Additional thanks to Dr. Coralee Tye and Natali Page for their help in RNA-seq analysis, Joseph Boyd for his assistance with bioinformatics analysis, and Kristiaan Finstad and Morgan Czaja for their help in animal studies. Thanks to Terri Messier for her kind help in the lab. Additional thanks to all current and previous members of the Stein-Lian laboratory, Nick, Gillian, Prachi, Kaleem, Jonathan, Kirsten, Mingu, Areg, Josh, Helena, Gileade, Phil, Hai, Xuhui, Rodrigo, Jennifer, Mark, Cesear, Ryan, Alex for their help with my projects and scientific discussions. I would like to thank my thesis research advisory committee members Dr. Leslie Shaw, Dr. Kendall Knight, Dr. Jeffrey Nickerson, Dr. Stephen Jones and my external committee Dr. Robert Weinberg and my committee chair Dr. Hong Zhang for their time, valuable input and support for my graduate studies and career development. I would like to extend my gratitude to my beloved parents Dr. Xiuping Hong and Dr. Yiping Sun for their unconditional love and support throughout my life. I also want to thank all of my friends for their support and company. iii Abstract Breast cancer remains the most common malignant disease in women worldwide. Despite the advantages of early detection and improved treatments, studies into the mechanisms that initiate and drive breast cancer progression are still required. Recent studies have identified RUNX1, which is an essential transcription factor for hematopoiesis, is one of the most frequently mutated genes in breast cancer patients. However, the role of RUNX1 in the mammary gland is understudied. In this dissertation, we examined the role of RUNX1 in both normal mammary epithelial and breast cancer cells. Our in vitro studies demonstrated that RUNX1 inhibits epithelial to mesenchymal transition (EMT), migration, and invasion, reflecting its tumor suppressor activity, which was confirmed in vivo. Moreover, RUNX1 also contributes significantly to inhibition of the phenotypes of breast cancer stem cells (CSC), which is responsible for metastasis and tumor relapse. We showed that Runx1 overexpression reduces the tumorsphere formation and cancer stem cell population. Overall, our studies provide mechanistic evidence for RUNX1 repression of EMT in mammary cells, anti-tumor activity in vivo and regulation of CSC-like properties in breast cancer. Our results highlight crucial roles for RUNX1 in preventing epithelial to mesenchymal transition and tumor progression in breast cancer. This RUNX1 mediated mechanism points to novel intervention strategies for early stage breast cancer. iv Table of Contents Acknowledgements……………………………………….…………….……..……………iii Abstract………………………………………………………………….……...……….…...iv Table of Contents...…………………………………………………………………............v List of Figures……………………………………………………………...…………......….x List of Tables…………………………………………………..…………………….……..xiii List of Symbols and Abbreviations………..……..…………………..……………….….xiv Preface……………………………………………….……………………………………..xvi CHAPTER I. Introduction…………………………………...…………………………...1-52 <ul style="display: flex;"><li style="flex:1">1.1 </li><li style="flex:1">The Introduction of Breast Cancer …………………………………………………1 </li></ul><ul style="display: flex;"><li style="flex:1">1.1.1 </li><li style="flex:1">Breast cancer overview………………………………………...……………1 </li></ul>Breast cancer molecular subtypes………………………………………....1 The origin of breast cancer and breast cancer subtypes………..………7 Cell line models used in breast cancer study………….........…………..11 1.1.2 1.1.3 1.1.4 <ul style="display: flex;"><li style="flex:1">1.2 </li><li style="flex:1">The Runx Family………………………………………………..……………....….12 </li></ul><ul style="display: flex;"><li style="flex:1">1.2.1 </li><li style="flex:1">Runx family overview……………………………..………...…………......12 </li></ul>Structure of Runx………………………………..………………………....14 Evolutionary role of Runx………………………..………………………...17 1.2.2 1.2.3 <ul style="display: flex;"><li style="flex:1">1.3 </li><li style="flex:1">The Runx Family and Development in Mammals…….........…………………..20 </li></ul><ul style="display: flex;"><li style="flex:1">1.3.1 </li><li style="flex:1">Overview……………………………………….……………………………20 </li></ul>Runx1………………………………………………..……………………….21 Runx2……………………………………………….……………………….24 Runx3………………………………………………….…………………….26 1.3.2 1.3.3 1.3.4 v1.4 1.5 1.6 The Runx Family in Disease and Cancer…………………….………………….27 <ul style="display: flex;"><li style="flex:1">1.4.1 </li><li style="flex:1">Overview………………………………………….…………………………27 </li></ul>Runx1………………………………………….…………………………….28 Runx2 and Runx3…………………………………………………....……..31 1.4.2 1.4.3 Runx1 and Mammary Gland Development and Breast Cancer……………....32 <ul style="display: flex;"><li style="flex:1">1.5.1 </li><li style="flex:1">Mammary gland development and hierarchy……………………………32 </li></ul>Runx1 and mammary gland development…………………...…………..33 Runx1 and breast cancer………….…………………………...………….34 1.5.2 1.5.3 Epithelial Mesenchymal Transition in Breast Cancer…………..………………38 <ul style="display: flex;"><li style="flex:1">1.6.1 </li><li style="flex:1">Overview of epithelial mesenchymal transition …………..…………….38 </li></ul>Epithelial mesenchymal transition in development…………..…………39 Epithelial mesenchymal transition in cancer………………….…………41 Runx and EMT………………………………………………….…………..43 1.6.2 1.6.3 1.6.4 <ul style="display: flex;"><li style="flex:1">1.7 </li><li style="flex:1">Cancer Stem Cell and Breast Cancer……………..………………..……………45 </li></ul><ul style="display: flex;"><li style="flex:1">1.7.1 </li><li style="flex:1">Intra-tumor heterogeneity………………………………….………………45 </li></ul>Cancer stem cells………………………………………….……………….47 EMT and plasticity and cancer stem cells……………………....……….49 1.7.2 1.7.3 1.8 Rationale for the Dissertation………………………………………..…………….…50 CHAPTER II. Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition……………………………...………53-101 2.1 Abstract……………………………………………………….………….……….…….54 2.2 Introduction…………………………………………….….……………….…………...55 2.3 Materials and Methods……………………………….……….……….….………..…58 vi 2.4 Results……………………………………………………………..…………....…...…66 2.4.1 Runx1 expression is decreased in breast cancer …………..……...….….…66 2.4.2 TGFβ induced EMT decreases Runx1 expression in MCF10A cells …..….69 2.4.3 Runx1 reverses the TGFβ-induced EMT phenotype……………..….….……72 2.4.4 Decreased expression of Runx1 during TGFβ independent EMT in MCF10A cells…………………………………………..………………..................…..……..74 2.4.5 Gene expression profiling of growth factor-depleted MCF10A cells reveals the spectrum of EMT markers………………………………………..…………..……77 2.4.6 Directly Depleting Runx1 in MCF10A cells results in loss of epithelial morphology and activation of EMT.………………….……………………………….……....…82 2.4.7 Depleting Runx1 in MCF7 breast cancer cells promotes EMT.…...….….…88 2.4.8 Overexpressing Runx1 in mesenchymal like breast cancer cells drives mesenchymal to epithelial transition (MET).…….……………………...…….…89 2.4.9 Runx1 expression in breast tumors correlates with metastasis, tumor subtype and survival…………………………………...…….…………………...……….…92 2.5 Discussion for Chapter II…………………………………………….….……...……..96 Chapter III RUNX1 Genome-wide Regulation of Normal Mammary Epithelial Cells: Novel Functions for Mitosis and Genome Stability……………………………………....102-146 3.1 Introduction……………………………………………...……………….……………106 3.2 Materials and Methods……………………………………………..…….....……….106 3.3 Results…………………………………………………………….………………......111 3.3.1. RUNX1 knockdown in normal-like mammary epithelial cells results in aberrant gene regulation …………………………………………………………….……..111 vii 3.3.2. Runx1 ChIP-seq analysis identifies enriched binding at promoters……...119 3.3.3. Runx1 binds to up- or down-regulated genes ………………………...…..122 3.3.4. Loss of RUNX1 affects cell cycle-related genes ……………..……….......127 3.3.5. Loss of RUNX1 decreases the proportion of mitotic cells……..……….…130 3.3.6. Loss of RUNX1 decreases genomic stability…………………….………..134 3.4 Discussion for Chapter III……………………………………………….…………...136 Chapter IV RUNX1 suppresses breast cancer stemness and tumor growth.…147-194 4.1 Abstract…………………………………………………………………….…...……..148 4.2 Introduction……………………………………………………………….…...………149 4.3 Materials and Methods…………………………………………………….....…..….152 4.4 Results……………………………………………………………………..……….....160 4.4.1. Reduced RUNX1 expression is associated with decreased survival probability in breast cancer patients ………………………………………………...………160 4.4.2. RUNX1 is decreased in tumors formed in mouse mammary fat pad…....165 4.4.3. RUNX1 reduces the aggressive phenotype of breast cancer cells……....168 4.4.4. RUNX1 represses tumor growth in vivo ……………..…………….............172 4.4.5. RUNX1 level is decreased in breast cancer stem cells (BCSC).……..….176 4.4.6. RUNX1 inhibits stemness properties in breast cancer cells……………..181 4.4.7. RUNX1 represses the expression of Zeb1 in breast cancer cells.…..…..185 4.5Discussion for Chapter IV………………………. …………………………...……..190 Chapter V Discussion and future direction….….………………...…….…………195-212 5.1 Results summary………………………………………………...…….……………..195 5.2 Significant and clinical impact …………………………………………..…………..197 viii 5.3. Open questions and future directions…..……..…………………………………..199 5.4. Concluding Remarks……………………………………….………………………………..212 Bibliography……………………………………………….……………………………….213 ix List of Figures Figure 1.1 Schematic model of mammary epithelial hierarchy and potential relationship with breast tumor subtypes. ………………………….….….……..………10 Figure 1.2 Structure of the CBF-b: Runt domain: DNA complex. ……..…….………..16 Figure 2.1. Decreased Runx1 expression is related to breast cancer progression in cell models…………………………...………………………………………………………..…68 Figure 2.2. Runx1 decreases during TGFβ-induced EMT. MCF10A cells treated with 10 ng/ml TGFβ for 6 days. ……………………………………………..………………….....71 Figure 2.3. Runx1 reverses TGFβ induced EMT ……………………………...….....…74 Figure 2.4. Decreased Runx1 during TGFβ-independent EMT ………………………76 Figure 2.5. RNA-Seq reveals MCF10A cells undergo EMT upon growth factor removal. ………………...…………………………………………………………………………......80 Figure 2.6. Increased Runx2 during growth factor depleted induced EMT. ………………………………...……………………………….……...……………………..82 Figure 2.7. Depleting Runx1 in MCF10A cells promotes a mesenchymal-like phenotype.………………………………………………………………………..….……...84 Figure 2.8. . Schematic diagram of ChIP qPCR primers and amplicons over the tested gene for ChIP-qPCR.……………… ……………………………………………………...87 Figure 2.9. Runx1 consensus sequences in CDH1 are coincident with H3K4Ac peaks in MCF10A cells ………………………………..……………………………………………..88 Figure 2.10. Runx1 controls EMT-MET in non-metastatic breast cancer cells. …………………………………….………………………………………………………….90 xFigure 2.11. Runx1 expression in breast tumors correlates with metastasis, tumor subtype and survival …………………………………………………………………………...……93 Figure 2.12 Runx1 tissue microarray show that Runx1 is associated with early stage tumor …………………………………………………………………...…………………...95 Figure 3.1 RNA-seq in RUNX1 depleted MCF10A cells. …………………….………113 Figure 3.2 The expression of mesenchymal genes is increased in RUNX1 depleted MCF10A cells……………………………………………………………..………..……...115 Figure 3.3 Defining differentially expressed genes in RUNX1 knockdown in MCF10A cells showing in Venn diagram. ………………………………………………………...116 Figure 3.4 IPA canonical pathway analyses from each tier of core analysis. ………………………………………………………………………………………………118 Figure 3.5 RUNX1 ChIP-seq in parental MCF10A cells. ………………………....….121 Figure 3.6 RUNX1 regulates up- and down- regulated genes in a different pattern.123 Figure 3.7 HOMER de novo motif analysis of the RUNX1 peaks in un-differentially expresses genes…………………………………………………………………………..126 Figure 3.8 RUNX1 alters the expression of cell cycle genes……….. ……………....129 Figure 3.9 Loss of RUNX1 reduces the mitotic population. ………………….………131 Figure 3.10 Runx1 is a direct regulator of Bub1b, MAD2L1 and APC…………..…..133 Figure 3.11 Loss of Runx1 slows DNA repair………………………………………….135 Figure 3.12 Runx1 is a direct regulator of Bub1b, MAD2L1 and APC………………142 Figure 3.13 Possible mechanisms of Runx1-controlled mitotic entry………………..146 Figure 4.1. Reduced RUNX1 expression is associated with decreased survival probability in breast cancer patients………………………………………………………………….162 xi Figure 4.2. RUNX1 mRNA is decreased during breast cancer progression..……..164 Figure 4.3. RUNX1 is decreased in tumors formed in mouse mammary fat pad….166 Figure 4.4. RUNX1 reduces the aggressive phenotype of breast cancer cells………… in vitro………………………………………………………………………………...……169 Figure 4.5. RUNX1 overexpression does not change cell proliferation……………..171 Figure 4.6. RUNX1 represses tumor growth in vivo…………………………………..174 Figure 4.7. RUNX1 represses tumor growth in mammary fat pad………………….175 Figure 4.8. Gate for MCF10AT1 sorting and MCF10CA1a cells have high BCSC population………………………………………………………………………………….177 Figure 4.9. RUNX1 level is decreased in BCSC……………………………………...178 Figure 4.10. CD24high Cells have high RUNX1 expression in MCF10AT1 cells.…180 Figure 4.11. Loss of RUNX1 promotes stemness in MCF10A and MCF7 cells……182 Figure 4.12. RUNX1 reduces BCSC sub-population………………………………….184 Figure 4.13. Overexpression RUNX1 in MCF10CA1a cells does not change BCSC population………………………………………………………………………………….185 Figure 4.14. RUNX1 negatively regulates Zeb1 expression…………………………187 Figure 4.15. Zeb1 is expressed at low level in MCF10CA1a cells…………………..189 Figure 4.16. Schematic diagram of ChIP qPCR primers and amplicons over Zeb1 for ChIP-qPCR………………………………………………………………………………...190 Figure 5.1 Potential Runx1 regulators locate within 1kb upstream of Runx1 promoter…………………………………………………………………………………....202 Figure 5.2 Heat map of changes in ribosome protein mRNAs……………………….205 xii List of Tables Table 1.1 Features of molecular subtypes of breast cancer..………………… ............3 Table 5.1. Table 5.1 List of LncRNAs which expression is changed upon Runx1 knockdown in MCF10A cells and their involvement in human breast cancer.…………………………………………………………….……...…………..……211 xiii List of Symbols and Abbreviations Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Aldehyde dehydrogenase (ALDH) Anaphase-promoting complex (APC) complex Breast cancer stem cell (BCSC) Caenorhabditis elegans (C.elegans) Cancer stem cell (CSC) Circulating tumor cell (CTC) Cleidocaranial dysplasia (CCD) Core-binding factor b (CBFb) Cyclin-dependent kinase 1 (CDK1) Drosophila melanogaster (Dm) Ductal carcinoma in situ (DCIS) Endothelial to hematopoietic transition (EHT) Epidermal growth factor (EGF) Epithelial-mesenchymal transition (EMT) Estrogen receptor (ER) Fibroblast-specific protein 1 (Fsp1) Hematopoietic stem cells (HSCs) xiv Hepatocyte growth factor (HGF) Human epidermal growth factor receptor 2 (HER2) Integrin-like kinase (ILK) Invasive ductal carcinoma (IDC) Long noncoding RNAs (lncRNAs) Mammary stem cells (MSC) Mesenchymal to epithelial transition (MET) Mitotic checkpoint complex (MCC) Myelodysplastic syndrome (MDS) Nervy homology regions (NHR) Polyoma enhancer-binding protein-2α (PEBP2α) Progesterone receptor (PR) Propidium iodide (PI) Standard error of the mean (SEM) Strongylocentrotus purpuratus (Sp) Sub-nuclear matrix-targeting signal (NMTS) The Cancer Genome Atlas (TCGA) Transcripts per million (TPM) Transforming growth factor beta (TGF-b) Triple-negative breast cancer (TNBC) xv Preface Portions of this thesis have appeared in the following published works: Chapter II: Hong D, Messier TL, Tye CE, Dobson JR, Fritz AJ, Sikora, KR, Browne G, Stein JL, Lian JB, Stein GS Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition. Oncotarget. 2017; 8:17610-17627 Other published work during graduate study that are not presented in this thesis: 1. Zaidi SK, Frietze SE, Gordon JA, Heath JL, Messier TL, Hong D, Boyd JR, Kang M, Imbalzano AN, Lian JB, Stein JL, Stein GS Bivalent Epigenetic ControlD of Oncofetal Gene Expression in Cancer. Molecular and Cellular Biology 2017 In press PMID: 28923849 2. Fritz AJ, Ghule PN, Boyd JR, Tye CE, Page NA, Hong D, Weinheimer AS, Barutcu AR, Gerrard DL, Frietze SE, Zaidi SK, Imbalzano AN, Lian JB, Stein JL, Stein GS Intranuclear and higher‐order chromatin organization of the major histone gene cluster in breast cancer Journal of cellular physiology 2017 In press PMID: 28504305 3. Barutcu AR, Hong D, Lajoie BR, McCord RP, van Wijnen AJ, Lian JB, Stein JL, Dekker J, Imbalzano AN, Stein GS RUNX1 associates with TAD boundaries and organizes higher order chromatin structure in breast cancer cells. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2016; 1859(11): 1389 4. Dobson JR, Hong D, Barutcu AR, Hai W, Anthony N Imbalzano, Lian JB, Stein JL, van Wijnen AJ, Nickerson JA, Stein GS Isolation and characterization of nuclear matrix-associated DNA in breast cancer cell lines. J Cell Physiol. 2017;232(6):1295. 5. Browne G, Dragon JA, Hong D, Messier TL, Gordon JA, Farina NH, Boyd JR, VanOudenhove JJ, Perez AW, Zaidi SK, Stein JL, Stein GS, Lian JB MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Tumour Biol. 2016; 37(7): 8825

RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes

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