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Transcriptional Alterations During Mammary Tumor Progression in Mice

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Transcriptional Alterations During Mammary Tumor Progression in Mice TRANSCRIPTIONAL ALTERATIONS DURING MAMMARY TUMOR PROGRESSION IN MICE AND HUMANS By Karen Fancher B.S. Hartwick College, 1995 A THESIS Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (Interdisciplinary in Functional Genomics and in Biomedical Sciences) The Graduate School The University of Maine December, 2008 Advisory Committee: Barbara B. Knowles Ph.D., Professor, The Jackson Laboratory, Co-Advisor Gary A. Churchill Ph.D., Professor, The Jackson Laboratory, Co-Advisor Keith W. Hutchison Ph.D., Professor of Biochemistry and Molecular Biology, The University of Maine, Thesis Committee Chair M. Kate Beard-Tisdale Ph.D., Professor of Spatial Information Science and Engineering, The University of Maine Shaoguang Li M.D., Ph.D., Associate Professor, The Jackson Laboratory LIBRARY RIGHTS STATEMENT In presenting this thesis in partial fulfillment of the requirements for an advanced degree at The University of Maine, I agree that the Library shall make it freely available for inspection. I further agree that permission for "fair use" copying of this thesis for scholarly purposes may be granted by the Librarian. It is understood that any copying or publication of this thesis for financial gain shall not be allowed without my written permission. Signature: Date: TRANSCRIPTIONAL ALTERATIONS DURING MAMMARY TUMOR PROGRESSION IN MICE AND HUMANS By Karen Fancher Thesis Co-Advisors: Dr. Barbara B. Knowles and Dr. Gary A. Churchill An Abstract of the Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (Interdisciplinary in Functional Genomics and in Biomedical Sciences) December, 2008 Family history, reproductive factors, hormonal exposures, and subjective immunohisto- chemical evaluations of in situ lesions, and to a lesser extent age, remain the best clinical predictors of an individual’s risk of developing breast cancer. Identification of early markers predictive of impending invasive breast cancer from in situ carcinoma is a long-term goal. The latent mammary cancer transgenic mouse model of human breast cancer, C57BL/6J- Tg(WapTAg)1Knw (Waptag1), develops characteristic stages of tumorigenesis in a highly predictable manner: atypical hyperplasia advances to ductal carcinoma in situ (DCIS), which progresses to papillary adenocarcinomas and/or solid, invasive tumors. Microarray analyses of whole mammary glands and tumors across these stages, to detect transcriptional changes throughout tumorigenesis, revealed marked, phased stage-specific changes. In contrast, results from the laser capture microdissected tumor cells depict a moderately constant characteristic tumorigenic profile, irrespective of stage. Evaluation of differences in whole glands with those of microdissected samples suggests that paracrine signaling between tumor and stromal cells substantially alters the tumor microenvironment, early in progression. Strikingly, comparison of statistically significant microarray results between Waptag1 DCIS and human DCIS revealed 2,097 overlapping early transcriptional changes. When compared with species-specific controls, common abundant early gene alterations were associated with cell cycle, cell division, and DNA replication Gene Ontology categories, with a notable decrease in genes involved in aerobic energy metabolism, and significant increased transcription of retrotransposons and chromosome modification genes. Based on these initial experimental results, retrotransposons were identified as a potential marker for testing in several mouse models and in biopsies derived from breast cancer patients. Analysis of data from five independent mouse models of mammary cancer and five human breast cancer datasets revealed over expression of retrotransposons, mainly Class I and Class II LTR elements, as well as LINEs and SINEs, when compared with normal samples. Cross-species comparison of gene expression profiles suggests epigenetic alterations and chromatin remodeling changes coincide with retrotransposon over expression. Through validation of such mutual human and mouse changes in gene expression, these novel putative markers may allow earlier detection and therapeutic intervention, possibly reducing the incidence of invasion and metastases in patients with breast cancer. ACKNOWLEDGEMENTS The research presented in this thesis was funded by CA34196, CA88327, and CA89713 from the National Institutes of Health; National Science Foundation IGERT Program Fellowship 0221625 (KSF, BBK-PI); Maine Cancer Foundation (BBK-PI); The University of Maine Graduate School of Biomedical Sciences and The Judith A. Lese Breast Cancer Foundation, Inc. Research presented here may be part of ongoing collaborations. Karen Fancher is indebted to Drs. D. Craig Allred and Sangjun Lee for generously sharing the human DCIS raw microarray data. She would like to acknowledge the exceptional opportunities she was offered by her mentors, Drs. Barbara B. Knowles and Gary A. Churchill, during her graduate studies. She is appreciative of the efforts of her graduate committee members as well. She is abundantly grateful to Drs. Igor Mikaelian, Carol Bult, Barbara Tennent, Alexei Evsikov, and Carrie Evsikova as well as summer student, Hannah Tetrault; their support helped her to accomplish this goal. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS...............................................................................................................ii LIST OF TABLES……………………………………………………..................................................vii LIST OF FIGURES…………………………………………………...................................................viii Chapter 1. INTRODUCTION......................................................................................................................1 1.1. Tumor Progression......................................................................................................1 1.2. Human Breast Carcinogenesis ...................................................................................1 1.3. The Experimental Hypothesis......................................................................................3 1.4. Mouse Models of Mammary Cancer.............................................................................3 1.5. In Situ Carcinoma Studies In Vivo...............................................................................6 1.6. SV40 Tumor Antigen (SV40 Tag)................................................................................7 1.7. Chromatin Remodeling, Retrotransposons and Cancer............................................11 1.8. Statistical Microarray Analysis...................................................................................17 1.9. Summary…………………………………………………………………………….……….23 2. MATERIALS AND METHODS.................................................................................................24 2.1. Mice and Samples......................................................................................................24 2.1.1. Mice............................................................................................................24 2.1.2. Whole mammary tumors and glands..........................................................24 2.1.3. Cryopreserved tumors and mammary glands.............................................25 2.1.4. Laser Capture Microdissected Samples.....................................................25 2.2. Microarrays.................................................................................................................28 2.2.1. Mouse.........................................................................................................28 2.2.2. Human........................................................................................................29 2.3. Statistical Experimental Design and Analysis.............................................................29 2.3.1. NIA 15K two-color microarrays (Waptag1 only)……………………….……...30 2.3.2. Affymetrix one-color microarrays (Waptag1 or human)…………….………..30 2.3.3. Survival Analysis.........................................................................................31 iii 2.4. Retrotransposons........................................................................................................32 2.4.1. Datasets……………………………………………………………….…………….....32 2.4.1.1. Mouse Microarrays……………………………………………….……………....32 2.4.1.2. Human Two Color Microarray Data…………………………….……………....32 2.4.1.3. Human Affymetrix Data……………………………………………….………....33 2.4.2. Classification………………………………………………………………….……….33 2.5. Cross-Species Comparisons......................................................................................34 2.6. Gene Ontology and Pathway Analysis.......................................................................34 2.6.1. VisuaL Annotation Display................................................................................34 2.6.2. GenMAPP Energy Pathway Analysis................................................................35 2.6.3. MouseCyc Pathway Representation………………….........................................35 3. CHARACTERIZATION OF WAPTAG1, A MOUSE MODEL OF DUCTAL CARCINOMA IN SITU WITH PROGRESSION TO INVASIVE CANCER.................................36 3.1. Waptag1 Tumorigenesis, a Multi-Stage Progressive Disease with Delayed-Onset............................................................................................................36 3.2. Waptag1 Whole Glands and Tumors Exhibit Stage-Specific Expression Profiles.....................................................................................................37
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