Using mouse models to understand the role of tumor suppressor genes in development and tumorigenesis

Breast cancer is the most common cancer in women in the western world, with approximately one in ten women developing this disease. In breast cancer development, both genetic and environmental factors play a role, with inheritance of high penetrance susceptibility genes, BRCA1 and BRCA2, accounting for approximately 5% of all cases. In order to understand the role of tumor suppressor genes in regulation of normal cell growth and in prevention of mammary tumor formation, I have taken a genetic approach, through the use of genetically engineered mice deficient in the expression of tumor suppressor genes Brca1, Trp53 , and Rb, to address specific questions concerning the pathophysiology of mammary carcinogenesis.; In this dissertation I address whether mammary tumorigenesis in mice is influenced by the loss of individual or sets of tumor suppressor genes, in combination with specific sets of modifier alleles present on inbred mouse strains. Mice heterozygous for a Trp53 mutation on an inbred BALB/c background are shown to be susceptible to mammary tumors, and both the tumor incidence and latency associated with these animals can be altered by hormonal stimulation, exposure to ionizing radiation, and introduction of a Brca1 mutation.; Furthermore, I show that similar interactions between tumor suppressor genes and modifier genes observed in normal cells also play an important role during the development of the embryo. Mice homozygous for a Brca1 mutation die in utero, and I show that the stage of development at which embryonic lethality occurs is altered not only by the severity of the introduced Brca1 mutation, but by the genetic background in which the Brca1 is bred. Finally, I show that heterozygosity for a mutant Trp53 allele is sufficient and equal to complete loss p53 function to maintain growth and survival of Brca1−/− embryos, thus allowing a small number of Brca1−/−Trp53−/− and Brca1−/−Trp53+/− mice to survive beyond parturition. These findings demonstrate the important roles that tumor suppressors like Brca1 and Trp53 play in regulation of cell growth and the prevention of tumorigenesis.