The role of GPNMB in breast tumor progression by April Ann Nicole Rose A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © April Rose, 2011 Faculty of Medicine Division of Experimental Medicine Montreal, Quebec, Canada II TABLE OF CONTENTS TABLE OF CONTENTS............................................................................................................III ABSTRACT .................................................................................................................................VI RÉSUMÉ ...................................................................................................................................VIII ACKNOWLEDGEMENTS .........................................................................................................X PUBLICATIONS ARISING FROM THIS WORK .............................................................XII CONTRIBUTIONS OF THE AUTHORS ........................................................................... XIII ORIGINAL CONTRIBUTIONS TO KNOWLEDGE....................................................... XIV PREFACE ....................................................................................................................................XV LIST OF FIGURES................................................................................................................ XVII LIST OF ABBREVIATIONS ................................................................................................... XX CHAPTER 1 - LITERATURE REVIEW & INTRODUCTION............................................. 1 1.1 CANCER DEFINITION & GLOBAL CANCER BURDEN .......................................................... 2 1.2 NORMAL BREAST TISSUE AND BREAST CANCER ................................................................ 2 1.2.1 Anatomy of the breast .................................................................................................... 2 1.2.2 Breast cancer statistics ................................................................................................... 3 1.2.3 Breast cancer risk factors................................................................................................ 4 1.2.4 Clinicopathological characterization of breast tumors ................................................... 4 1.2.5 Established prognostic factors for breast cancer............................................................. 5 1.2.6 Emerging prognostic indicators..................................................................................... 9 1.2.7 Molecular subtypes as predictive factors for breast cancer .......................................... 12 1.3 ANGIOGENESIS.................................................................................................................... 16 1.4 METASTASIS ........................................................................................................................ 18 1.4.1 Theories of metastatic progression ............................................................................... 18 1.4.2. Bone Metastases .......................................................................................................... 21 1.4.3 Soft tissue and visceral metastases............................................................................... 27 1.4.2 Mouse models of breast cancer metastasis ................................................................... 29 1.5 GPNMB .............................................................................................................................. 31 1.5.1 Identification of GPNMB and its orthologues ............................................................. 31 1.5.2 Structure and function of GPNMB ............................................................................. 32 1.5.3 Post-translational modification of GPNMB ................................................................ 36 1.5.4 Putative GPNMB ligands............................................................................................ 38 1.5.5 GPNMB expression and function in normal tissue types ........................................... 40 1.5.6 Regulation of GPNMB expression............................................................................... 42 1.5.7 GPNMB expression and function in cancer ................................................................ 43 1.5.8 CDX-011...................................................................................................................... 46 III 1.6 SUMMARY............................................................................................................................ 49 1.7 REFERENCES ........................................................................................................................ 50 1.8 FIGURES AND LEGENDS...................................................................................................... 63 1.8.1 Figure Legends ............................................................................................................. 63 1.8.2 Figures.......................................................................................................................... 65 CHAPTER 2 - OSTEOACTIVIN PROMOTES BREAST CANCER METASTASIS TO BONE............................................................................................................................................ 68 PREFACE.................................................................................................................................... 69 ABSTRACT ................................................................................................................................. 70 INTRODUCTION......................................................................................................................... 71 RESULTS..................................................................................................................................... 73 DISCUSSION............................................................................................................................... 82 MATERIALS AND METHODS ..................................................................................................... 87 ACKNOWLEDGEMENTS ............................................................................................................ 94 REFERENCES.............................................................................................................................. 95 FIGURES LEGENDS .................................................................................................................... 99 FIGURES ................................................................................................................................... 105 CHAPTER 3 – GLYCOPROTEIN NONMETASTATIC B IS AN INDEPENDENT PROGNOSTIC INDICATOR OF RECURRENCE AND A NOVEL THERAPEUTIC TARGET IN BREAST CANCER ........................................................................................... 114 PREFACE.................................................................................................................................. 115 ABSTRACT ............................................................................................................................... 116 TRANSLATIONAL RELEVANCE............................................................................................... 117 INTRODUCTION....................................................................................................................... 118 RESULTS................................................................................................................................... 119 DISCUSSION............................................................................................................................. 124 MATERIALS AND METHODS................................................................................................... 127 ACKNOWLEDGEMENTS .......................................................................................................... 132 REFERENCES............................................................................................................................ 133 TABLES .................................................................................................................................... 135 FIGURES LEGENDS .................................................................................................................. 135 FIGURES ................................................................................................................................... 139 SUPPLEMENTAL MATERIALS AND METHODS ....................................................................... 144 SUPPLEMENTARY TABLES ...................................................................................................... 146 SUPPLEMENTAL FIGURE LEGENDS ........................................................................................ 151 SUPPLEMENTAL FIGURES ....................................................................................................... 154 SUPPLEMENTAL REFERENCES ................................................................................................ 160 CHAPTER 4 - ADAM10 RELEASES A SOLUBLE FORM OF THE GPNMB/OSTEOACTIVIN EXTRACELLULAR DOMAIN WITH ANGIOGENIC PROPERTIES ............................................................................................................................ 161