Omega-6 Fat Promotion of Mutant Kras-Induced Pancreatic Neoplasia

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DESCRIPTION (provided by applicant): Pancreatic cancer has the poorest survival of any known cancer, and current therapies are insufficient. A novel approach to fighting this disease involves chemoprevention, where dietary intake of fats and inhibition of key enzymes may reduce production of early cancer before it spreads. To test this approach, mice that develop early pancreatic cancer will be fed high fat diets where the ratio of w-3:w-6 fats vary. Observing disease progression and correlating gene expression with specific molecular mechanisms is the focus of this project. Understanding the process and molecular mechanisms behind the role of w-6 fat in the development and progression of mutant Kras-induced pancreatic intraepithelial neoplasms (PanINs) will illuminate dietary effects on pancreatic cancer development in the human population. Pancreatic cancer is a formidable foe and is the fourth leading cause of cancer deaths, where the annual incidence and mortality are about equal at ~30,000 people per year. In this proposal, we will address the effect of w-6 polyunsaturated fatty acids (PUFA) following an initiating event in pancreatic cancer etiology, a mutation in Kras, which leads to increased expression of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2). These enzymes are associated with the arachidonic acid (AA) pathway and utilize PUFAs as substrates for the production of leukotrienes and prostaglandins. Hence, ?-6 PUFAs will affect the ability of mutant Kras to mediate cellular changes that lead to early neoplasia through the AA metabolic enzymes, 5-LOX and COX-2. We hypothesize that EL-Kras transgenic mice will develop greater incidence, frequency, and shorter time of onset for PanIN development when administered a diet rich in w-6 fats (1:8) when compared to cohorts of EL-Kras mice administered a diet rich in omega-3 fats (8:1 w-3:w-6 ratio). We further hypothesize that these effects are due to provision of substrates available to the AA metabolic enzymes, 5-LOX and COX-2, which will be proven by establishing EL-Kras mice with no expression of 5-LOX and/or COX-2 and administered diets with low and high w-3:w-6 ratio of fat. Ultimately, we will determine if the absence of 5-LOX and/or COX-2 can prohibit the effects of w-6 fats on PanIN formation in EL-Kras mice. In addition, rodent diets with high w-6 fats change the expression of many genes including some found altered in pancreatic cancer. We intend to demonstrate that a 1:8 w-3:w-6 fat ratio in the diet of these mice will increase IGF-II, IGFBP-1, and GLUT-1 and decrease H19, FAS, and RAR¿ expression leading to higher rates of cell division, lower rates of apoptosis, and increased glucose metabolism. Reduced PanIN formation in mice deficient for 5LOX and/or COX-2 will provide the impetus for inhibiting these enzymes in the clinic. Altered gene expression in this panel of genes with concomitant cellular effects independent of 5-LOX and COX-2 would support the use of a potential alternative and/or combined strategy with inhibition of IGF-II, IGFBP-1, and/or GLUT-1. This project will investigate the role of high fat diets on the progression of early pancreatic cancer, relating it to inflammatory mediators and the type or ratio of fat consumed. Mice that develop early pancreatic precancer will be administered high fat diets (w-3:w-6 fatty acid ratios 1:8 , 1:1, and 8:1) and studied for enhanced or suppressed development of pancreatic precancer. Results from this work will establish potential pathways that, when altered by drugs or changes in the diet, may prevent or retard the development of pancreatic cancer.