Tumor suppressor dysregulation in mouse models of tumorigenesis

This work addresses several ways that mutations in tumor suppressor genes and oncogenes lead to cancer. There are many pathways that when dysregulated can result in caner, such as loss of function of tumor suppressors such as p53, Atm, and Brca1 or from the gain of function mutation of oncogenes such as Ras and Myc. However, the mechanisms of these aberrations are numerous and complex to say the least.;Chapter 1 of this dissertation reviews some background of the field of tumor biology, especially as it refers to mouse models of human disease relating to tumor suppressors and oncogenes. Chapter 2 discusses findings in Atm deficient murine T-cell tumor cells in which chromosomal abnormalities were discovered to contribute to the cancer phenotype. Chapter 3 discusses a different mechanism of tumorigenesis in which the protein, Mnt, acts as a tumor suppressor in direct opposition to the well-characterized oncogene, c-Myc by competitively binding to promoter regions thereby dysregulating transcriptional regulation. Chapter 4 presents findings that heterozygosity of the tumor suppressor Atm acts to exacerbate tumor phenotypes and developmental abnormalities in mammary tissue that lacks Brca1, mimicking a common form of human hereditary mammary gland cancer. These findings suggest that when this cancer-prone tissue is haploinsufficient for Atm, tumors that arise are less differentiated and more invasive. The developing mammary gland also shows a delay in ductal branching, which is unseen in Brca1 deficient mammary glands lacking the secondary Atm mutation. Chapter 5 summarizes and contrasts the findings that these three different mechanisms contribute to tumorigenesis in mouse models of human cancer.