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 fet al (zeta) globin promoter and uniquely responds to chemical carcinogen s and tumor promoters by the induction of epidermal papillomas, Althou gh 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 spont aneous tumors, including odontomas, squamous cell carcinoma of the sal ivary gland, leukemias and a rare ovarian yolk sac carcinoma, Both spo ntaneous and induced tumors are associated with expression of the tran sgene and, as determined by in situ hybridization, transgene expressio n is localized to proliferative areas of the tumors, Sequence analysis of the endogenous c-Ha-ras gene in both induced and spontaneous tumor s revealed no mutations in codons 12, 59 or 61, These results suggest that expression of the v-Ha-ras transgene induces proliferation of spe cific cells in diverse tissues which then acquire neoplastic propertie s.