PCB 153, a Non-dioxin–like Tumor Promoter, Selects for β-Catenin (Catnb)–Mutated Mouse Liver Tumors

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants which act as liver tumor promoters in rodents and can be classified as either dioxin-like or non-dioxin (phenobarbital [PB])–like inducers of cytochrome P-450. Since we have previously shown that tumor promotion by PB leads to clonal outgrowth of β-catenin (Catnb)–mutated but not Ha-ras–mutated mouse liver tumors, we were interested to know whether the non-dioxin–like tumor promoter 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB 153) shows the same selective pressure during tumor promotion. Male B6129SF2/J mice were given a single injection of N-nitrosodiethylamine (90 mg/kg body weight) at 9 weeks of age, followed by 39 weeks of treatment with PCB 153 (20 biweekly ip injections of 300 μmol/kg body weight) or corn oil as a control. Animals were killed 15 weeks after the last PCB 153 injection and liver tumors were identified by immunohistochemical staining of glutamine synthetase (GS) and analyzed for Catnb, Ha-ras, and B-raf mutations. Quantitative analyses revealed that GS-positive tumors were much larger and more frequent in livers from PCB 153–treated mice than in control animals, whereas GS-negative tumors were similar in both groups. Almost 90% (34/38) of all tumors from PCB 153–treated animals contained Catnb mutations, which compares to ∼ 45% (17/37) of tumors in the control group. Ha-ras– and B-raf–mutated liver tumors were rare and not significantly different between treatment groups. These results clearly indicate that PCB 153 strongly selects for Catnb-mutated, GS-positive liver tumors, which is similar to the known action of PB, a prototypical tumor promoter in rodent liver.