Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48^Cre/+-LSL-Kras^G12D/+mice

Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1) transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC). Six-week-old female p48^Cre/+-LSL-Kras^G12D/+ and compound Fat-1-p48^Cre/+-LSL-Kras^G12D/+ mice were fed (AIN-76A) diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P <.02) in Fat-1-p48^Cre/+-LSL-Kras^G12D/+ mice compared to p48^Cre/+-LSL-Kras^G12D/+ mice. Importantly, significant reductions of pancreatic ducts with carcinoma (90%; P <.0001) and PanIN 3 (~50%; P <.001) lesions were observed in the compound transgenic mice. The levels of n-3 PUFA were much higher (>85%; P <.05-0.01) in pancreas of compound transgenic mice than in those of p48^Cre/+-LSL-Kras^G12D/+ mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX), 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48^Cre/+-LSL-Kras^G12D/+ mice compared to p48^Cre/+-LSL-Kras^G12D/+ mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals.