The effect of dietary n-3 and n-6 polyunsaturated fatty acids on the expression of cyclooxygenase 1 and 2 and levels of p21ras in rat mammary glands

Dietary n-6 polyunsaturated fatty acids (PUFAs) promote rat mammary cancer while n-3 PUFAs are inhibitory. The purpose of this study was to determine whether the fats exert their effects by altering the expression of genes that affect cancer development. Therefore, we have examined the effect of PUFAs on the expression of the cyclooxygenase (COX) 1 and 2 genes that are involved in prostaglandin biosynthesis. We also investigated the effect of dietary PUFAs on the expression of the p21ras protein and Ha-ras mRNA. Rats were fed either low- (7%; LF) or high- (21%; HF) fat diets that were rich in either n-6 PUFAs (safflower oil, S) or n-3 PUFAs (menhaden oil, M) for 3 weeks. COX-1 mRNA levels were approximately the same in groups fed diets containing either level of menhaden oil, but were increased by approximately 30% in the LFS and HFS groups (P0.05). Transcripts of the inducible COX-2 gene were not detectable in the menhaden oil groups, but this gene was expressed in animals fed either level of safflower oil and in the HFS group was associated with increased levels of COX enzymatic activity and production of PGE2. Animals fed safflower oil had elevated levels of p21ras protein compared to animals fed menhaden oil. Ha-ras mRNA was increased by approximately 35% in animals fed HFS compared to the group fed HFM (P0.05). These results demonstrate that dietary n-6 PUFAs upregulate COX-2 and, to some extent, COX-1 expression. There was a concomitant increase in COX enzyme activity and PG synthesis in the mammary glands of rats fed high levels of n-6 PUFAs. Together with associated changes in p21ras expression, these results may explain, at least in part, the promoting effects of dietary n-6 PUFAs on mammary carcinogenesis.