C-RAF EXPRESSION IN EARLY RAT-LIVER TUMORIGENESIS AFTER PROMOTION WITH POLYCHLORINATED-BIPHENYLS OR PHENOBARBITAL

1. The expression of c-raf protooncogene in early stages of chemically induced rat liver tumorigenesis was studied in weanling female and adult male Sprague-Dawley rats. After initiation with diethylnitrosamine, promotion by polychlorinated biphenyls (PCBs) or phenobarbital (PB) was studied in the female. Male rats were promoted with PCBs only. 2. The incidence of enzyme-altered foci was evaluated histochemically by demonstrating a deficiency in adenosine-5'-triphosphatase and the emergence of gamma-glutamyltranspeptidase. C-raf expression was measured in liver tissue containing preneoplastic foci, and in small (< 3 mm in diameter) and large(> 3 mm in diameter) neoplastic nodules up to 36 weeks. 3. Foci numbers amounted to 60-70 per cm(2) liver section with both histochemical markers and both promoters in female rats. In male rats foci numbers were about 20-40 per cm(2) liver section with both markers and with PCBs as promoting agents. Foci area developed more rapidly in female rats. 4. Small and large nodules were found in females during the entire observation period with both promoting agents, PCBs being more effective than PB. C-raf expression in nodules was increased up to 10-fold in PCB-treated animals compared with untreated controls. No dependence on the size of the nodules was seen. In male rats nodule incidence was very low and c-raf induction was marginal. 5. In conclusion c-raf proto-oncogene expression correlated with the incidence of foci and nodules, female rats being more sensitive than males.