Previous studies have examined the role of mouse mammary tumor virus in development of mammary adenocarcinomas. Correlation of viral gene expression and segregating genetic markers among recombinant inbred (RI) mice indicated possible trans regulation of viral RNA expression. In this proposal the interaction of viral and nonviral loci in the induction of mammary tumor viruses will be the primary objective. In addition, our preliminary finding of a MMTV-related human tumor virus, will be examined further by studies of the structure and distribution of this sequence. The analysis of virus-specific RNA in RI mice revealed that several genetic markers unlinked to viral sequences were significantly associated with high expression. Of these the Lps locus was the most significant (p 0.0001). This locus is responsible for a pleitropic response of the cell to lipopolysaccharide (LPS). The possible trans regulation of the virus by this gene will be examined extensively. The molecular mechanism of this process will be explored as will the involvement in the turmorigenic process. In addition, genetic experiments examining the role of other viral and nonviral loci in viral gene regulation and oncogenesis are described. These experiments involve genetic crosses among inbred mice, between inbred virus positive and a new MMTV-negative mouse, and hybrid somatic cells. Studies of tumorigenesis will examine the number and structure of viral DNA sequences, their DNA methylation, and RNA expression. In preliminary studies we have identified a viral sequence in human cells. This virus is included sequences which are greater than 90% homologous with that of the MMTV envelope gene. This human tumor virus is polymorphic in the small sample of human DNAs tested thus far. Experiments are proposed that will clone and characterize this sequence and that will determine its distribution in normal and high risk human populations.
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