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Analysis of Novel Targets in the Pathobiology of Prostate Cancer

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Analysis of Novel Targets in the Pathobiology of Prostate Cancer ANALYSIS OF NOVEL TARGETS IN THE PATHOBIOLOGY OF PROSTATE CANCER by Katherine Elizabeth Bright D’Antonio B.S. in Biology, Gettysburg College, 2002 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cellular and Molecular Pathology University of Pittsburgh 2008 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This thesis was presented by Katherine D’Antonio It was defended on April 13, 2009 and approved by Beth Pflug, PhD, Associate Professor of Urology Luyuan Li, PhD, Associate Professor of Pathology George Michalopoulos, MD, PhD, Professor of Pathology Dan Johnson, PhD, Associate Professor of Medicine Dissertation Advisor: Robert Getzenberg, PhD, Professor of Urology ii Copyright © by Katherine D’Antonio 2009 iii ANALYSIS OF NOVEL TARGETS IN THE PATHOBIOLOGY OF PROSTATE CANCER Katherine D’Antonio, PhD University of Pittsburgh, 2009 The process of developing a greater understanding of the fundamental molecular mechanisms involved in prostate carcinogenesis will provide insights into the questions that still plague the field of prostate cancer research. The goal of this study was to identify altered genes that may have utility either as biomarkers, for improved diagnostic or prognostic application, or as novel targets important in the pathobiology of prostate cancer. We hypothesize that an improved understanding of the genomic and proteomic alterations associated with prostate cancer will facilitate the identification of novel biomarkers and molecular pathways critical to prostate carcinogenesis. In order to enhance our knowledge of the molecular alterations associated with prostate cancer, our laboratory performed microarray analysis comparing gene expression in healthy normal prostate to that in prostate cancer tissue. Of the greater than 400 genes with significantly altered expression identified in our study, MT2A, Tacc2, Nell2, FosB, PCP4, and Cyr61 were selected for further evaluation to confirm expression changes and evaluate their potential impact in prostate cancer. Analysis of MT2A, Tacc2, and Nell2 expression patterns failed to demonstrate significant changes between prostate cancer and donor prostate tissue and, therefore, these results do not support their further development as prostate cancer biomarkers. We demonstrated that PCP4 was expressed predominently in the stromal compartment of the prostate and was expressed at similar levels in the stroma of normal and prostate cancer tissue. Interestingly, protein expression of PCP4 in a panel of colon cancer tissues was dramatically iv higher in adenoma and adenocarcinoma tissues compared to donor and benign colon tissue and, consequently, we feel that PCP4 has more potential as a biomarker in colon cancer than in prostate cancer. We also demonstrated that FosB and Cyr61 were upregulated in prostate cancer tissues over donor prostate tissues. Based on expression analysis of FosB and expression and functional analysis of Cyr61, we believe that these two targets have the greatest potental to be functionally significant in the etiology of prostate cancer. v TABLE OF CONTENTS PREFACE...................................................................................................................................XV 1.0 INTRODUCTION........................................................................................................ 1 1.1 PROSTATE GLAND .......................................................................................... 1 1.2 MALE REPRODUCTIVE SYSTEM ................................................................ 5 1.3 PROSTATE DEVELOPMENT ......................................................................... 6 1.4 PROSTATIC DISEASE...................................................................................... 7 1.4.1 Prostatitis....................................................................................................... 7 1.4.2 Benign Prostatic Hyperplasia ...................................................................... 9 1.5 PATHOBIOLOGY OF CANCER ................................................................... 11 1.5.1 Expression Changes, A Hallmark of Cancer............................................ 11 1.5.2 Metastasis..................................................................................................... 13 1.6 PROSTATE CANCER...................................................................................... 15 1.6.1 Risk Factors................................................................................................. 20 1.6.2 Diagnostics................................................................................................... 22 1.6.3 Stage and Grade.......................................................................................... 22 1.6.4 Genetics........................................................................................................ 26 1.6.5 Treatment .................................................................................................... 27 1.7 PROSTATE CANCER BIOMARKERS......................................................... 29 vi 1.7.1 The Issue of Over-Treatment..................................................................... 29 1.7.2 Prostate Specific Antigen ........................................................................... 30 1.7.3 Prostate Cancer Antigen 3 ......................................................................... 33 1.7.4 Alpha-methylacyl-CoA Racemase............................................................. 34 1.7.5 Early Prostate Cancer Antigen 2............................................................... 35 2.0 PROJECT BACKGROUND AND METHODS...................................................... 36 2.1 HYPOTHESIS ................................................................................................... 36 2.2 TARGET GENES MODIFIED IN PROSTATE CANCER.......................... 37 2.2.1 Metallothionein 2A...................................................................................... 37 2.2.2 Transformin, acidic coiled-coiled containing protein 2........................... 38 2.2.3 Nell2.............................................................................................................. 39 2.2.4 FosB.............................................................................................................. 42 2.2.5 Purkinje Cell Protein 4............................................................................... 44 2.2.6 Cysteine-rich, angiogenic inducer, 61 ....................................................... 44 2.2.6.1 CCN protein family............................................................................. 44 2.2.6.2 The normal role of Cyr61................................................................... 45 2.2.6.3 Cyr61 in disease................................................................................... 46 2.2.6.4 Cyr61 in cancer ................................................................................... 46 2.3 MATERIALS AND METHODS...................................................................... 47 2.3.1 Cell Culture ................................................................................................. 47 2.3.2 Tissues and Tissue Microarrays ................................................................ 47 2.3.3 Immunohistochemistry............................................................................... 48 2.3.4 Scoring and TMA Analysis ........................................................................ 49 vii 2.3.5 Nested Case-Control Study: Rational, Parameters and Tissues ............ 50 2.3.6 Protein Isolation.......................................................................................... 53 2.3.7 Immunoblot Analysis.................................................................................. 54 2.3.8 RNA Isolation.............................................................................................. 55 2.3.9 Semi-quantitative PCR............................................................................... 56 2.3.10 Quantitative PCR........................................................................................ 57 2.3.11 Cloning......................................................................................................... 59 2.3.12 Transient and Stable Transfection............................................................ 60 2.3.13 Microarray Analysis ................................................................................... 61 2.3.14 Growth and Survival Assays...................................................................... 62 2.3.15 Cell Doubling Time..................................................................................... 62 2.3.16 Migration and Invasion .............................................................................. 63 2.3.17 Statistical Analysis ...................................................................................... 64 3.0 GENE EXPRESSION CHANGES IN PROSTATE CANCER............................. 65 3.1 INTRODUCTION ............................................................................................. 65 3.2 RESULTS ........................................................................................................... 66 3.2.1 Expression of MT2A in prostate cancer ................................................... 66 3.2.2 Expression of Tacc2 in prostate cancer ...................................................
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