Mouse lung tumor is valuable as a biological model for studying tumor susceptibility, stages of tumor development, and the interaction of genetic and environmental factors which dispose towards neoplasia. Recently, it has been postulated that the process of carcinogenesis in lung tissue may involve at least three genetic events: 1) the genetic predisposition which may contribute to the onset or susceptibility to the development of cancer; 2) the activation of cellular oncogenes; and 3) the inactivation of tumor suppressor genes. the strain A mouse has a high incidence of spontaneous lung tumors and is susceptible to lung tumor induction by chemical carcinogens. A high frequency of activated K-ras proto-oncogenes has recently been detected in both spontaneously occurring and chemically induced lung tumors in strain A mice. More recently, an allele (from A/J parent)-specific activation of the K-ras gene in lung tumors from (C3H X A/J)F1 and (A/J X C3H)F1 mice was observed. the objective of this research is to delineate mechanisms of this allele-specific activation of K-ras gene in lung tumors from mouse hybrids.
The specific aims are (1) to determine DNA sequence differences between the lung tumor susceptible and resistant strains of mice; (2) to determine allele-specific expression of K-ras gene in hybrid mouse lung tumors; (3) to study the regulation of K-ras gene transcription; (4) to determine allele-specific methylation of K-ras gene in mouse hybrids; and (5) to determine activation of K-ras gene in recombinant inbred mice. The proposed studies will provide evidence for mechanisms of lung tumor susceptibility, allele-specific activation of K-ras oncogene, and regulation of K-ras oncogene expression in the development of mouse lung tumors. This study will have significant implications on our understanding of why certain populations are predisposed to develop specific types of cancer.
