Mammary Cancer Promotion and MAPK Activation Associated With Consumption of a Corn Oil-Based High-Fat Diet

Abstract

Our earlier work has shown a selective promotional effect on the genesis of mammary carcinomas bearing a wild-type, but not mutant, Ha-ras codon 12 in a 1-methyl-1-nitrosourea (MNU)-induced carcinogenesis model by high-fat diets (Nutr Cancer 23, 283-290, 1995). To test the hypothesis that activation of the mitogen-activated protein kinase (MAPK) pathway is associated with this promotional effect, we compared the in vivo MAPK phosphorylation state of carcinomas from rats consuming a low-fat (5% corn oil, modified AIN-93G) with that from rats consuming a high-fat (25% corn oil) diet. Specifically, 21-day-old female Sprague-Dawley rats were given an intraperitoneal injection of MNU and one week later were randomized to the two diets for six weeks. The number of mammary carcinomas per rat was 68% greater in the high-fat group, and Ha-ras mutation was rare in this short-term model. The levels of the phosphorylated MAPK2 (active) and of proliferating cell nuclear antigen (PCNA) were significantly higher in carcinomas from the high-fat group, and the two parameters were substantially correlated (r2 = 0.43, p < 0.01). The expression level of c-Raf was fourfold higher in the high-fat group but was only modestly associated with MAPK activation (r2 = 0.35, p < 0.05). The levels of the total MAPK1 and MAPK2, guanosine triphosphatase-activating protein, Ha-Ras, and MAPK kinase did not change. These results suggest that an upregulation of c-Raf expression by high fat may in part account for the in vivo MAPK activation, which in turn may enhance cell proliferation and mammary carcinogenesis.

Dietary intake alters gene expression in colon tissue

“…We found meat consumption to be associated with TP53, NFκB1, and MAPK signaling through the ERK1/2 signaling pathway. The Ras-MAPK system is involved in cell proliferation 61 ; moreover, our findings in this network are consistent with earlier findings that high-fat diets, the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhiP), and sodium nitrate can activate the MAPK pathways 9 , 16 , 62 . Nonmeat consumption appears to play a greater role in the regulation of the PI3K complex, TNF-signaling, and TGFB1-signaling pathways.…”

“…Diet has been associated with several diseases including atherosclerosis 1 , 2 , inflammatory bowel disease 3 , steatosis and nonalcoholic fatty liver disease 4 , 5 , seizures 6 , and various cancers including colon and breast carcinoma 7 – 9 . Moreover, diet has also been identified as a risk factor for type 2 diabetes mellitus, obesity, and metabolic syndrome 10 .…”

Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle

“…Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. An increased incidence of cancer with high-fat diet has been reported in experimental animals (30). Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes.…”

Liver mitochondrial properties from the obesity-resistant Lou/C rat

“…43 Indeed, high levels of unsaturated fat were found, among others, to increase oxidative stress and decrease antioxidative enzyme Low caloric intake and liver mitochondria G Lacraz et al activity. 44 In contrast, energy restriction was reported to reduce tumor incidence even in animals fed a high-fat diet, 45 suggesting that oxidative stress linked to high-fat intake can be modulated by adjusting caloric intake.…”