Synergism between bovine papillomavirus type 4 and the flavonoid quercetin in cell transformation in vitro.

Bovine papillomavirus type 4 (BPV-4) morphologically transforms primary bovine cells in vitro only in the presence of an activated ras gene. The transformed cells are capable of anchorage-independent growth, but are not immortal and are incapable of inducing tumors in nude mice, suggesting that other events are needed to convert the cells to the fully transformed phenotype. We show here that treatment of the cells with a single dose of the flavonoid quercetin leads to full oncogenic transformation of cells transfected with BPV-4 and ras. Quercetin is one of the most potent mutagens found in bracken fern, the environmental cofactor in BPV-4-associated carcinogenesis of the upper alimentary canal of cattle. Our results point to quercetin as the probable in vivo cocarcinogen synergizing with BPV-4 in malignant progression.