Abstract PL02-01: Energy balance and cancer prevention: Mechanistic insights from mutant mice

Abstract

Abstract The prevalence of obesity, an established risk and progression factor for many cancers, has risen steadily during the past several decades in the US and many other countries. Unfortunately, the mechanisms underlying the obesity and cancer connection are not well understood, and new targets and strategies for offsetting the impact of obesity on cancer risk are urgently needed. Calorie restriction (CR), the most commonly recommended dietary strategy for preventing or reversing obesity, inhibits spontaneous, transplanted and chemically induced tumors in a variety of animal models. In contrast, diet-induced obesity enhances tumorigenesis in many of these same models. We demonstrated in a series of transgenic mouse model systems and microarray studies that the insulin-like growth factor (IGF)-1 pathway appears central to many of the anticancer effects of CR and procancer effects of obesity. Using AZIP/F1 transgenic mice (which lack white adipose tissue but have high levels of insulin, IGF-1 and inflammatory markers), and liver-specific IGF-1-deficient mice, we showed that components of the IGF-1 and inflammatory pathways (independent of the adipose tissue per se) are important targets for disrupting the obesity-cancer link. Also, genetic or pharmacologic (rapamaycin, metformin) inhibition of the Akt/mammalian target of rapamycin (mTOR) pathway in murine models of breast, skin and pancreatic cancer blocks the effects of obesity on tumor development and progression. We are currently conducting parallel studies in high-risk human subjects and relevant animal models to further elucidate underlying mechanisms, biomarkers, and effective interventions for offsetting the effects of obesity on cancer. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PL02-01.