Suppression of ethylnitrosourea-induced Schwannoma development involves elimination of neu/erbB-2 mutant premalignant cells in the resistant BDIV ratstrain

Contrary to the response of rats of the highly sensitive inbred strain BDIX , BDIV rats are resistant to the induction of malignant schwannomas by expo sure to the alkylating N-nitroso carcinogen N-ethyl-N-nitrosourea (EtNU), I n BDIX rats, a point mutation at nucleotide 2012 in the transmembrane regio n of the neu/erbB-2 gene has proved to be a very early marker of initiated Schwann precursor cells with an elevated risk of malignant transformation, and is diagnostic of the resulting schwannomas, To gain insight into the ce llular and molecular mechanisms responsible for the resistance of the BDIV strain, comparative quantitative neu mutation analyses combined with histom orphological studies were performed on the trigeminal nerves of EtNU-treate d BDIV and BDIX rats as well as on their (BDIX x BDIV) F-1 progeny. It was found that nea-mutant Schwann cells are initially present at comparable fre quency in the trigeminal nerves of both resistant and sensitive animals. Co ntrasting with the progressive multiplication of mutant Schwann cells in BD IX trigeminal nerves, however, the numbers of mutant cells began to decreas e during the intermediary phase of the carcinogenic process in BDIV animals , and premalignant nea-mutant cells were no longer detectable by the time B DIX rats developed full-blown trigeminal schwannomas. The resistance of BDI V rats thus involves the elimination of initiated neu-mutant Schwann cells during the postinitiation period of EtNU-induced schwannomagenesis via mech anisms that remain to be clarified.