Transgenic mice and host cell mutants resistant to transformation as model systems for identifying multiple...

Tumorigenesis appears to be a multistep process involving mutations of conventional, dominantly acting proto-oncogenes, mutations of other genes that may act in a recessive manner, and interactions (or a lack of interactions) between the products of mutant and wild-type genes. Our laboratory is using a few well-established, dominant oncogenes to pose experimental questions that could lead to a better understanding of the more elusive genetic interactions which occur during tumour development. Two such situations are described: (1) We have created a line of transgenic mice that carry the int-1 proto-oncogene under the control of the enhancer element in the mouse mammary tumour virus long terminal repeat. Such mice express the transgene in mammary glands, salivary glands and male reproductive tract; mammary glands from both male and female animals are grossly hyperplastic, yet tumours arise rarely in the males and sporadically in the females (80% of female mice have one or a few tumours by six months of age). Thus expression of int-1 in these mice appears to place a large number of mammary cells at risk for secondary events that lead to carcinogenesis, providing a provocative experimental context for identifying such secondary events. (2) We have isolated a rat cell line that lacks most of the characteristics of transformed cells, despite the expression of two wild-type copies of the v-src gene of Rous sarcoma virus. This line harbours what appears to be a dominant mutation in an unidentified gene that renders the cell resistant to transformation by v-src and several other oncogenes. Isolation of the mutant gene responsible for suppressing transformation in this line should provide new insights into the interactions between oncoproteins and other cellular proteins.