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  • Title: Effect of dietary fat on codon 12 and 13 Ha-ras gene mutations in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary gland tumors.
    Author: Roberts-Thomson SJ, Snyderwine EG.
    Journal: Mol Carcinog; 1997 Dec; 20(4):348-54. PubMed ID: 9433479.
    Abstract:
    Activating mutations in and expression of the Ha-ras gene were examined in benign and malignant female Sprague-Dawley rat mammary gland tumors induced by the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by a diet high in polyunsaturated fat. Ha-ras mutations were detected in codons 12 and 13 by selective polymerase chain reaction amplification of mutated sequences and nucleotide sequencing. The percentage of Ha-ras mutations in carcinomas from PhIP-treated rats was significantly higher in rats on a low-fat diet than in rats on a high-fat diet (82% (nine of 11) vs 26% (seven of 27), respectively, P < 0.01). In addition, whereas 56% of the carcinomas with Ha-ras mutations from rats on a low-fat diet carried double Ha-ras mutations, none of the carcinomas from rats on a high-fat diet had double mutations. Ha-ras mutations were also detected in benign tumors (largely adenomas) induced by PhIP in rats on different diets; two of eight and three of four benign tumors examined from rats on low-fat and high-fat diets, respectively, had Ha-ras mutations, suggesting that activating Ha-ras mutations alone are not sufficient for PhIP-induced tumors to become malignant. No differences were observed in the level of Ha-ras mRNA expression in the different groups. In our animal model, a high-fat diet increased the incidence and percentage of malignant PhIP-induced mammary gland tumors yet decreased the percentage of carcinomas showing Ha-ras mutations. Thus, the complement of genetic alterations associated with PhIP-induced mammary gland carcinogenesis is probably altered by the level of dietary fat.
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