Mechanisms underlying cell-fate determination in the mammary gland development
نویسنده
چکیده
.................................................................................................................................................... 5 RÉSUMÉ .......................................................................................................................................................... 7 ACKNOWLEDGMENTS ................................................................................................................................ 9 ABBREVIATIONS ...................................................................................................................................... 11 CHAPTER I: INTRODUCTION ................................................................................................................ 13 BREAST CANCER ........................................................................................................................................................................ 15 Breast Cancer: An Overview ............................................................................................................................................................ 15 Breast Cancer Development and Stages ..................................................................................................................................... 15 Breast Cancer Subtypes ..................................................................................................................................................................... 16 MAMMARY GLAND ..................................................................................................................................................................... 19 Mammary Gland: An Overview ...................................................................................................................................................... 19 Mammary gland as a model organ .............................................................................................................................................. 19 Mammary Gland Development ...................................................................................................................................................... 20 Mammary Epithelium Structure ................................................................................................................................................... 24 Hormonal regulation ......................................................................................................................................................................... 26 Stem cells and epithelial cell hierarchy ...................................................................................................................................... 28 Differentiation of Mammary epithelial cells ............................................................................................................................. 30 NOTCH SIGNALING ..................................................................................................................................................................... 30 Discovery of Notch signaling and its implications in development ................................................................................. 30 Notch Receptors ................................................................................................................................................................................... 32 Notch Ligands ....................................................................................................................................................................................... 33 Basic mechanism of Notch signaling pathways ...................................................................................................................... 33 Target Genes .......................................................................................................................................................................................... 36 Notch in Human Cancers .................................................................................................................................................................. 37 Tumor Suppressive Notch Signaling ............................................................................................................................................ 37 Notch in Mammary gland ................................................................................................................................................................ 38 Notch in Breast Cancer...................................................................................................................................................................... 40 P63 .............................................................................................................................................................................................. 44 Gene structure ...................................................................................................................................................................................... 44 p63 in development ............................................................................................................................................................................ 45 p63 in mammary gland ..................................................................................................................................................................... 46 p63 and cell adhesion in mammary epithelial cells ............................................................................................................... 47 CHAPTER II: AIM OF THE THESIS AND RESULTS ........................................................................... 49 AIM OF THE PROJECT ................................................................................................................................................................. 51 AIM1: ROLE OF NOTCH SIGNALING IN THE MOUSE MAMMARY GLAND ............................................................................. 53 Endogenous Notch activity in the mouse mammary gland (Transgenic Notch reporter mouse model) ......... 53 Conditional deletion of RBP-Jκ gene in the Wnt4 expressing subpopulation of HR+ cells (RBPfloxed Wnt4-Cre mTmG mouse model). ........................................................................................................................................................................ 66 Conditional deletion of RBP-Jκ gene in the whole mammary epithelium (RBPfloxed MMTV-Cre mTmG mouse model). ..................................................................................................................................................................................................... 80 Time directed conditional deletion of RBP-Jκ in the mammary epithelium (Intraductal injection of AdenoCre virus into RBP-Jκfloxed mTmG mouse model) ...................................................................................................................... 93 Inhibition of canonical Notch signaling in the endogenous mammary epithelium via intraductal injection of γ-secretase inhibitor DAPT ............................................................................................................................................................105 Bioinformatical analysis of the mouse Progesterone receptor promoter ...................................................................108
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