Association of tumor development with increased cellular proliferation and transgene overexpression, but not c-Ha-ras mutations, in v-Ha-ras transgenic Tg.AC mice.

The transgenic mouse line Tg.AC carries a v-Ha-ras gene fused to a fetal (zeta) globin promoter and uniquely responds to chemical carcinogens and tumor promoters by the induction of epidermal papillomas. Although the transgene was not constitutively expressed in non-tumor-bearing tissues, expression was induced by exposure to selected chemicals. Tg.AC transgenic mice on the FVB/N background developed occasional spontaneous tumors, including odontomas, squamous cell carcinoma of the salivary gland, leukemias and a rare ovarian yolk sac carcinoma. Both spontaneous and induced tumors are associated with expression of the transgene and, as determined by in situ hybridization, transgene expression is localized to proliferative areas of the tumors. Sequence analysis of the endogenous c-Ha-ras gene in both induced and spontaneous tumors revealed no mutations in codons 12, 59 or 61. These results suggest that expression of the v-Ha-ras transgene induces proliferation of specific cells in diverse tissues which then acquire neoplastic properties.