EFFECTS OF GENETIC AND EPIGENETIC EVENTS ON MUTANT KRAS-INDUCED CARCINOMA IN SITU.

Abstract

Advances in the modeling of pancreatic cancer in mice have produced several systems that can be employed to address the contribution of multiple genetic events and epigenetic or dietary effects on pancreatic carcinogenesis. One such model, the EL-Kras transgenic mouse, develops mouse pancreatic intra-epithelial neoplasia, (mPanINs or ductal carcinoma in situ) which mimic human PanINs. Using this model, subtle to aggressive changes in phenotype were observed when altering the diet, modifying a single gene, or changing the genetic background. EL-Kras mice on a diet high in omega-6 fatty acids (23% corn oil compared to 3–5% for standard chows) developed multiple (2–4) mPanINs at 9–10 months at an incidence of 0.5 compared to usually only a single mPanIN at over 12 months at an incidence of 0.5. Introducing a dominant negative transgene that reduces the level of TGFβ RII signaling (thus recapitulating partial loss of smad 4) in EL-Kras (FVB) mice leads to the development of multiple (2–4) mPanINs at 5–6 months at an incidence of 0.5. Finally, EL-Kras mice (derived in the FVB background) were crossed one generation into the C57BL/6 (B6) background to generate EL-Kras FVB6 F1. This single cross produced the most aggressive change in phenotype including multiple (average 10–11) mPanINs appearing at 5–6 months in every mouse. Hence, time of onset was cut in half while the frequency was increased 10-fold and the incidence was doubled. With regard to the development of human PanINs, this data implies that genetic background has a prominent role in pancreatic carcinogenesis. Furthermore, single genetic events and diet can alter disease progression. Future work aims at combining these effects (EL-Kras/TGFβ dominant negative) FVB6 F1 on a high corn oil diet) to determine how multiple genetic and epigenetic changes affect PanIN and cancer development in mice.