The study of experimentally induced mammary tumors has focused primarily on several mouse strains that are infected with the mouse mammary tumor virus (MMTV) and have been bred for a high incidence of mammary tumors. MMTV appears to induce tumors by acting as an insertional mutagen that leads to the activation of a previously silent gene or the rearrangement of a normally expressed gene (int genes). We have found that the frequency with which different int genes are activated in mammary tumors depends on the particular strain of mice. For instance, 80% of the C3H mammary tumors contain a viral induced rearrangement of the int-I locus, whereas, in BALB/cfC3H mammary tumors the int-1 gene is rearranged in only 30% of the tumors. This suggests that the inbreeding program has selected for the fixation of a host mutation which somehow compliments the action of int-I gene expression during tumor development. We have expanded our studies to include the feral CZECHII mouse strain, which lacks endogenous MMTV genomes in its germline but is congenitally infected with exogenous MMTV. Several viral induced preneoplastic hyperplastic outgrowth (HOG) lines have also been developed. Three of these have been found to have a viral insertion at int-1. A new int locus, designated int-6, has been found in a fourth HOG line. Many of the HOG lines spontaneously give rise to mammary tumors and, in two independent cases, the mice also contained metastatic lesions in their lungs. The primary tumors frequently contain additional viral insertions over those observed in the particular HOG line. Similarly, the metastatic tumors frequently contain additional viral insertions over those observed in the primary tumor and the particular HOG line. This suggests that we may be able to identify new int genes that are associated with the particular stages of malignant progression. We have shown in other studies that the int-2 gene product can functionally replace bFGF and compete with it for cellular receptors. Work previously reported under Project number Z01 CB 09027 has been incorporated into this project.
