THE EFFECT OF DIETARY N-3 AND N-6 POLYUNSATURATED FATTY-ACIDS ON THE EXPRESSION OF CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 AND LEVELS OF P21(RAS) IN RAT MAMMARY-GLANDS

Dietary n-6 polyunsaturated fatty acids (PUFAs) promote rat mammary ca ncer while n-3 PUFAs are inhibitory, The purpose of this study was to determine whether the fats exert their effects by altering the express ion of genes that affect cancer development, Therefore, we have examin ed 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 p21( ras) protein and Na-ras mRNA, Rats were fed either low- (7%; LF) or hi gh- (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 leve l of menhaden oil, but were increased by similar to 30% in the LFS and ms groups (P < 0.05), Transcripts of the inducible COX-2 gene were no t detectable in the menhaden oil groups, but this gene was expressed i n animals fed either level of safflower oil and in the ms group was as sociated with increased levels of COX enzymatic activity and productio n of PGE(2). Animals fed safflower oil had elevated levels of p21(ras) protein compared to animals fed menhaden oil, Ha-ras mRNA was increas ed by similar to 35% in animals fed HFS compared to the group fed HFM (P < 0.05), These results demonstrate that dietary n-6 PUFAs upregulat e COX-2 and, to some extent, COX-I expression. There was a concomitant increase in COX enzyme activity and PG synthesis in the mammary gland s of rats fed high levels of n-6 PUFAs, Together with associated chang es in p21(ras) expression, these results may explain, at least in part , the promoting effects of dietary n-6 PUFAs on mammary carcinogenesis .