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Role of Jagged1 in the Enrichment of Cancer Stem Cells in HER2+ Breast Cancer Deep Shah Loyola University Chicago, Deep [email protected]

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Role of Jagged1 in the Enrichment of Cancer Stem Cells in HER2+ Breast Cancer Deep Shah Loyola University Chicago, Deep Pharma2010@Yahoo.In Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2017 Role of Jagged1 in the Enrichment of Cancer Stem Cells in HER2+ Breast Cancer Deep Shah Loyola University Chicago, [email protected] Recommended Citation Shah, Deep, "Role of Jagged1 in the Enrichment of Cancer Stem Cells in HER2+ Breast Cancer" (2017). Dissertations. 2854. https://ecommons.luc.edu/luc_diss/2854 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. Copyright © 2017 Deep Shah LOYOLA UNIVERSITY CHICAGO ROLE OF JAGGED1 IN THE ENRICHMENT OF CANCER STEM CELLS IN HER2+ BREAST CANCER A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN MOLECULAR PHARMACOLOGY AND THERAPEUTICS BY DEEP S. SHAH CHICAGO, ILLINOIS DECEMBER 2017 TABLE OF CONTENTS LIST OF FIGURES .......................................................................................... v LIST OF TABLES ............................................................................................ vii LIST OF ABBREVIATIONS ............................................................................. viii CHAPTER I: INTRODUCTION ........................................................................ 1 Anatomy of the Human Breast ..................................................................... 1 Breast Cancer .............................................................................................. 2 Risk Factors for Breast Cancer .................................................................... 2 Breast cancer risk factors that are not under personal control. ................. 2 Genetic risk factors. ................................................................................ 3 Lifestyle-related breast cancer risk factors. ............................................... 4 Subtypes of Breast Cancer .......................................................................... 5 Luminal A. ................................................................................................. 6 Luminal B. ................................................................................................. 7 Triple Negative. ......................................................................................... 8 Normal Breast-Like. ................................................................................... 10 Human Epidermal Growth Factor Receptor 2 (HER2). .............................. 10 HER2+ Breast Cancer: Drug Resistance ..................................................... 16 HER2 Mutations. ....................................................................................... 16 Activation of Compensatory Signal Transduction Pathways. .................... 17 Receptor tyrosine kinases. ..................................................................... 17 Intracellular kinases. ............................................................................... 19 Defects in Apoptosis and Cell Cycle Control. ............................................ 20 Involvement of Host Factors that Modulate Drug Response. .................... 22 Conclusion ................................................................................................... 22 CHAPTER II: CANCER STEM CELLS (CSCs) AND NOTCH SIGNALING: A LITERATURE REVIEW ................................................................................ 25 The CSC Hypothesis .................................................................................... 25 Proposed Markers to Identify Breast CSCs. .............................................. 26 HER2+ Breast CSCs. ................................................................................ 29 EMT and CSCs. ........................................................................................ 31 CSCs and Tumor Microenvironment. ........................................................ 32 Notch Signaling: A Literature Review ........................................................... 34 Introduction. .............................................................................................. 34 Notch Signaling Pathway. ......................................................................... 35 Notch receptors. ..................................................................................... 35 Notch ligands. ......................................................................................... 36 Jagged1. ................................................................................................ 37 Canonical Notch Signaling Pathway. ......................................................... 38 Notch Signaling in Mammary Gland Development. ................................... 41 Notch Signaling in Cancer. ........................................................................ 43 Notch Signaling and Breast Cancer. ......................................................... 44 Notch Signaling and Breast CSCs. ............................................................ 46 Crosstalk of Notch Signaling with Other Signaling Pathways in Breast Cancer. ................................................................................................... 47 ii Conclusion ................................................................................................... 50 CHAPTER III: MATERIALS AND METHODS ................................................. 55 Cell Culture .................................................................................................. 55 Drugs, Chemicals, and Reagents ................................................................. 56 RNA Interference and Transfection Reagents .............................................. 57 Antibodies .................................................................................................... 58 Western Blot Analysis .................................................................................. 59 Flow Cytometry ............................................................................................ 62 Cell Sorting ................................................................................................... 64 Aldefluor Assay ............................................................................................ 65 Mammosphere Assay ................................................................................... 66 Preparation of Methyl Cellulose Based Mammosphere Medium ............... 66 Mammosphere Assay Protocol .................................................................. 66 In Vivo Study ................................................................................................ 68 Immunohistochemical Staining of Human HER2+ Breast Tumors ............... 69 Real-Time PCR ............................................................................................ 70 Statistical Analysis ........................................................................................ 72 CHAPTER IV: HYPOTHESIS AND SPECIFIC AIMS ...................................... 74 CHAPTER V: RESULTS ................................................................................. 78 Specific Aim 1-Determine Whether Surface Expression of Jagged1 Is Critical for the Formation of CSCs ............................................................. 78 Aim 1A-Determine Whether Jagged1-High Subpopulation Upon Lapatinib Treatment Results in an Increase in the Formation of CSCs as Compared to Jagged1-Low Subpopulation in the Absence of Lapatinib Treatment. CSCs Would be Assessed by Mammosphere Forming Efficiency, Aldehyde Dehydrogenase Activity and the Levels of CD44 High/CD24 Low. ..................................................................................... 90 Jagged1-high subpopulation shows enhanced mammosphere formation upon HER2 inhibition, as compared to Jagged1-low subpopulation in the absence of HER2 inhibition. ............................ 90 Jagged1-high subpopulation upon HER2 inhibition shows an enhancement of aldehyde dehydrogenase positive CSCs, as compared to Jagged1-low subpopulation in the absence of HER2 inhibition. .......................................................................................... 92 Upon HER2 inhibition, Jagged1-high subpopulation doesn’t show a significant change in the levels of CD44 high/CD24 low CSCs, as compared to Jagged1-low subpopulation in the absence of HER2 inhibition. .......................................................................................... 93 Aim 1B-Assess Whether Jagged1 is Necessary for Lapatinib Mediated Enrichment of Mammospheres in the HER2+ Subtype of Breast Cancer. ................................................................................................... 100 Jagged1 is necessary for lapatinib mediated enrichment of mammospheres. ............................................................................... 100 Aim 1C-Measure the degree of Notch activation in Jagged1-high subpopulation upon lapatinib treatment and in the Jagged1-low iii subpopulation in the absence of lapatinib treatment. ............................. 104 The Jagged1-high subpopulation in the presence of lapatinib mediated HER2 inhibition has higher Notch activation, as compared to the Jagged1-low subpopulation, in the absence of HER2 inhibition. .........................................................................................
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