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Dissertation Christian Ruiz Identification and validation of novel amplification target genes in human breast cancer Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Christian Ruiz aus Spanien Basel 2006 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Markus A. Rüegg, Prof. Dr. Guido Sauter und Prof. Dr. Ruth Chiquet-Ehrismann Basel, den 19. Dezember 2006 Prof. Dr. Hans-Peter Hauri Dekan 2 TABLE OF CONTENTS Table of contents ACKNOWLEDGEMENTS.................................................................................................................. 5 ABBREVIATIONS ............................................................................................................................... 6 SUMMARY............................................................................................................................................ 7 1. INTRODUCTION............................................................................................................................. 8 1.1. Importance of this work ................................................................................................................... 8 1.2. Breast Cancer ................................................................................................................................... 9 1.2.1. Medical view ............................................................................................................................. 9 1.2.1.1. Classification of breast tumors ......................................................................................... 10 1.2.2. Molecular biological view....................................................................................................... 12 1.2.2.1. Biomarkers in breast cancer ............................................................................................. 16 1.2.2.2. Molecular expression patterns in breast cancer................................................................ 18 1.3. Gene amplification in cancer.......................................................................................................... 20 1.3.1. Mechanism of gene amplification ........................................................................................... 21 1.3.2. Detection of gene amplifications............................................................................................. 22 1.4. Validation of candidate genes ........................................................................................................ 25 1.4.1. Tissue microarrays .................................................................................................................. 25 1.4.2. Protein lysate microarrays....................................................................................................... 27 1.5. Aims of the thesis........................................................................................................................... 29 2. RESULTS......................................................................................................................................... 30 2.1. Part A: Tissue microarrays for comparing molecular features with proliferation activity in breast cancer (publication) ............................................................................................................. 30 2.2. Part B: Screening for new amplifications in breast cancer............................................................. 36 2.2.1. Overview of the project........................................................................................................... 36 2.2.2. Discovery of unrecognized amplified regions through development of a novel analysis procedure ................................................................................................................... 38 2.2.2.1. Analysis of the breast cancer data set with known methods ............................................ 38 2.2.2.2. Our new analysis procedure ............................................................................................. 39 2.2.2.3. New analysis method leads to the discovery of unrecognized amplifications in breast cancer..................................................................................................................... 41 2.2.3. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer and predicts response to tamoxifen (manuscript)........................................................................... 44 2.2.4. Nuclear Factor 1 B (NFIB) as target gene of the 9p24 amplification in human breast cancer (manuscript) ................................................................................................................. 66 TABLE OF CONTENTS 3. DISCUSSION .................................................................................................................................. 98 3.1. Conclusion.................................................................................................................................... 104 4. REFERENCES .............................................................................................................................. 105 5. APPENDIX .................................................................................................................................... 111 5.1. Evaluation of reverse phase protein microarrays (lysate microarrays) ........................................ 111 5.1.1. Introduction ........................................................................................................................... 111 5.1.2. Establishment of the best settings.......................................................................................... 111 5.1.3. The Her-2 experiment ........................................................................................................... 112 5.1.4. Discussion ............................................................................................................................. 113 CURRICULUM VITAE ................................................................................................................... 116 4 ACKNOWLEDGEMENTS Acknowledgements I am deeply grateful to Prof. Guido Sauter for giving me the opportunity to perform my thesis in his research group and for giving me such an important and exciting research topic. I am also very grateful to PD Dr. Ronald Simon for supervising me during my thesis and for his unique way of motivation. I would also like to thank Prof. Luigi Terracciano for hosting me during the last part of my thesis. Further, I would like to thank Prof. Ruth Chiquet-Ehrismann for being member of my thesis committee, for supporting me during my thesis and for helpful scientific suggestions. I would also like to express special thanks to PD Dr. Gertraud Orend for the first guidance in the world of science and for being member of my thesis committee. I am also deeply grateful to Prof. Markus Rüegg for being member of my thesis committee. Further, I would like to thank Dr. Michel Bihl for scientific discussions and suggestions. I am very grateful to my colleague Dr. Martin Oeggerli for sharing office, laboratories and scientific knowledge with me, for helping with the design and the layout of this document, and for enjoying so many hundreds of coffees together. Warm thanks to the members of the laboratories, for technical help and for sharing their time with me: Alex Rufle, Barbara Stalder, Sandra Schneider, Hedvika Novotny and Rosi Chaffard. Special thanks to my parents for unlimited care and generous support. Last but not least, I would like to thank Rebecca Schirinzi for supporting me since 1995. 5 ABBREVIATIONS Abbreviations DCIS ductal carcinoma in situ LCIS lobular carcinoma in situ IDC infiltrating ductal carcinoma ILC infiltrating lobular carcinoma ER estrogen receptor 1 protein ESR1 estrogen receptor 1 gene PR progesterone receptor HER-2 erythroblastic leukaemia viral oncogene homolog 2 (ERBB2) CGH comparative genomic hybridization aCGH array based comparative genomic hybridization FISH fluorescence in-situ hybridization SNP single nucleotide polymorphism NFIB nuclear factor 1 B IHC immunohistochemistry cdk cyclin-dependent kinase CAM cell-cell adhesion molecule MMP matrix metalloproteinase DM double minute HSR homogeneously staining region H&E haematoxylin and eosin BAC bacterial artificial chromosome RNAi RNA interference FCS fetal calf serum 6 SUMMARY Summary Gene amplification is a major mechanism for overexpression of potential oncogenes in cancer. Several amplifications have already been described in breast cancer. In order to find new amplified regions, we screened 30 human breast tumors for gene amplifications using the Affymetrix SNP 10k 2.0 microarrays. For this purpose, we developed a new analysis procedure leading to an increased signal- to-noise ratio which allowed us the discovery of new small single gene amplicons (< 1 Mb). Two of them, the ESR1 gene on 6q25 and the NFIB gene on 9p24, were further investigated. Fluorescence in- situ hybridization of these two genes was performed on a TMA comprising more than 2200 breast cancer samples. NFIB amplification was found in 5% of all breast cancers analyzed, but with an increased amplification rate in medullary carcinoma (19%). NFIB amplified breast cancers showed a higher Ki67 proliferation index. Functional analysis with RNA interference of
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