Heterozygous inactivation of TGF-beta 1 increases the susceptibility to chemically induced mouse lung tumorigenesis independently of mutational activation of K-ras

Mice heterozygous for deletion of the transforming growth factor beta1 (TGF -beta1) gene show an enhanced rate of lung tumorigenesis following carcinog en treatment. Since the growth inhibitory activity of TGF-beta1 in epitheli al cells is associated with K-ras p21, and K-ras mutations commonly occur i n chemically-induced mouse lung tumors, we postulated that tumors in hetero zygous TGF-beta1 mice might be more likely to have K-ras mutations compared with tumors in wildtype TGF-beta1 mice. Urethane-induced lung tumors in AJ BL6 TGF-beta1 + / - and + / + mice were examined for K-ras mutations by pol ymerase chain reaction/single strand conformation polymorphism analysis and sequencing. Mutation frequencies were similar in both genotypes: 12/18 + / - tumors (67%) and 10/16 + / + tumors (62%). Mutations occurred in 80% + / - and 75% + / + carcinomas, but in only 50% of the adenomas of both TGF-P I genotypes. Codon 61 A --> G transition mutations were predominant, occurr ing in 61% + / - and 44% + / + tumors. Three + / - (17%) and three + / + (1 9%) tumors showed codon 12 mutations, mostly G -->A transitions. Two + tumo rs had both codon 61 and codon 12 mutations. Interestingly, carcinomas with mutations in codon 61 were larger than those with codon 12 changes. It app ears that the mechanism of enhanced susceptibility of TGF-beta1 + / - mice to urethane-induced lung carcinogenesis does not involve selective developm ent of tumors with K-ras mutations. Published by Elsevier Science Ireland L td.