High Susceptibility of Human c-Ha-ras Proto-oncogene Transgenic Rats to Carcinogenesis

Abstract

Transgenic animals carrying human c-Ha-ras proto-oncogene, v-Ha-ras transgenic mice, pim-1 transgenic mice have been shown to exhibit increased carcinogen susceptibility. Based on this characteristics, studies aimed for application to medium-term screening with from 20 to 30 weeks duration for various environmental carcinogens are under way in many institutes. On the other hand, rat models are advantageous by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have generated transgenic rats carrying copies of the human c-Ha-ras proto-oncogene (Hras128) and shown to be extremely sensitive to mammary, and to a lesser extent, lesions in the urinary bladder, oesophagus and skin carcinogenesis. In most of mammary carcinomas, mutations of the transgene but not the endogenous H-ras gene are present, appearing to occur early in the process of carcinogenesis, which involves proliferation of cells in terminal end buds (TEBs) . Further findings suggest that this is independent of endogenous ovarian hormones, although inhibited by soy isoflavones. Although further studies of mechanistic aspect are clearly necessary, the model appears to have great potential for short-to long-term screening purposes, not only for modifiers active in the breast, but also other organs where tumors develop characterized by ras gene mutations.