Experiments are proposed to investigate the role of the Ras-mitogen activated protein kinase (MAPK) signal transduction pathway in mediating the mammary cancer promotional activity of Linoleic acid (LA), a prominent fatty acid present in the typical Western type diets. We have observed that, compared to a low fat diet, feeding a LA-rich, corn oil-based high fat diet resulted in a significant increase in the number of N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinomas without a Ha-ras codon 12 G A mutation (wild type at codon 12, abbreviated as Wtras 12), but no change of those with the mutation (mras12). We hypothesize that LA or its metabolites exert this selective promotional effect through interactions with the Ras- MAPK pathway.
AIM 1 will test the hypothesis that LA or its metabolites promote mammary carcinogenesis through an upregulation of the expression of Raf-1 and MAPKK2 and the resulting MAPK activation.
AIM 2 will test the hypothesis that LA or its metabolites (e.g., phosphatidic acids) enhance the in vivo Ras activity by interfering with the Ras/GAP interaction and the increased in vivo Ras activity accounts for MAPK activation and cancer promotion. The in vivo approaches proposed include examining the effect of increasing LA intake on MNU-induced carcinogenesis and the expression of the MAPK cascade components; effect of intraductal infusion of LA or its metabolites into mammary glands on Ras and MAPK activities, and gene transcriptional regulation; and the effect of retroviral mediated Raf-1 gene transfer on MNU-induced carcinogenesis. The high fat-human breast cancer connection is highly controversial, yet animal studies have consistently shown a mammary cancer promotional activity of high fat diets rich in LA. The research in this proposal may provide a strong rationale for a paradigm shift in fat- associated cancer risk assessment to be based on the intake of specific fatty acids, rather than of total fat, and the pathogenetic pathways that initiate and promote cancer development. If our hypothesis is valid and is extrapolatable to human carcinogenesis, a strong justification can be made for recommending that specific populations of individuals at risk for breast cancer modify their fat consumption pattern or reduce fat intake to achieve gene/pathway-specific prevention.
| Wang, Z; Pei, H; Kaeck, M et al. (1999) Mammary cancer promotion and MAPK activation associated with consumption of a corn oil-based high-fat diet. Nutr Cancer 34:140-6 |
