| Contents | 5 |
|---|
| Contributors | 6 |
|---|
| 1 Insertional Mutagenesis: A Powerful Tool in Cancer Research | 8 |
|---|
| 1.1 Introduction | 8 |
| 1.2 Historical Perspective | 9 |
| 1.3 The Site of Insertion can Provide Mechanistic Insights | 11 |
| 1.4 Methodologies | 12 |
| 1.5 Pairing Insertional Mutagenesis with Other Genetic Tools | 15 |
| 1.6 Mining Hidden Information in Mutagenesis Screens | 17 |
| 1.7 Importance of Thorough Bioinformatics Analysis | 19 |
| 1.8 The Added Value of Large Numbers | 20 |
| 1.9 Crossvalidation with Other Genetic Datasets | 20 |
| 1.10 Are New Cancer Causing Pathways to be Found | 21 |
| 1.11 Conclusions and Recommendations | 22 |
| References | 23 |
| 2 Retroviral Insertional Mutagenesis in Mouse Models of Leukemia and Lymphoma | 26 |
|---|
| 2.1 Introduction to the Murine Leukemia Viruses | 26 |
| 2.2 Viral and Host Determinants of Disease | 28 |
| 2.3 Challenges in MLV Mutagenesis Studies | 30 |
| 2.4 Comparative Oncogenomics | 36 |
| 2.5 Validation of Candidates | 38 |
| 2.6 Do Murine Retroviruses Cause Human Cancer | 40 |
| 2.7 Summary and Future Perspectives | 40 |
| References | 41 |
| 3 Gene Discovery by MMTV Mediated Insertional Mutagenesis | 46 |
|---|
| 3.1 Introduction | 46 |
| 3.1.1 Mouse Mammary Gland Biology | 48 |
| 3.1.2 Mouse Mammary Tumor Virus | 48 |
| 3.1.3 Viral Genes and Genomic Organization | 50 |
| 3.1.4 Transcription and Translation of the Viral Genes | 51 |
| 3.1.5 Virion Structure and Assembly | 52 |
| 3.1.6 Infectious Life Cycle | 53 |
| 3.1.7 Tissue Specificity and Hormonal Regulation of MMTV Replication | 54 |
| 3.1.8 Exogenous MMTV | 55 |
| 3.1.9 Endogenous MMTV | 56 |
| 3.1.10 MMTV-Induced Tumors | 56 |
| 3.1.11 MMTV Induced Hormone Dependent Premalignant Lesions | 57 |
| 3.1.12 Hormone-Dependent Mammary Tumors and MMTV | 58 |
| 3.1.13 MMTV-Induced Tumors in other Tissues | 58 |
| 3.2 Gene Discovery by MMTV Mediated Insertional Mutagenesis | 59 |
| 3.2.1 Common Integration Sites | 59 |
| 3.2.2 Modes by Which Insertional Mutagenesis Affects Cancer Genes | 60 |
| 3.3
|