The prevalence of obesity, an established risk and progression factor for many cancers, has more than doubled over the past three decades in the US, with ~36% of adults currently obese. The mechanisms underlying the obesity and cancer connection are becoming increasingly clear and reveal several potential targets and strategies for breaking the obesity-cancer link. We have established in multiple genetically engineered mouse models (GEMMs) of mammary, pancreatic and other epithelial cancers that diet-induced obesity (DIO) increases serum levels of bioavailable insulin-like growth factor (IGF)-1, induces insulin resistance, and enhances tumor development and progression. In contrast the maintenance of a lean phenotype via a calorie restriction (CR) regimen decreases IGF-1 levels, improves insulin sensitivity, and inhibits cancer development and progression in these same models. Furthermore, biochemical, genetic and pharmacologic studies in GEMMS further suggest components of the mammalian target of rapamycin (mTOR) pathway, downstream of insulin and IGF-1 receptors, interact with inflammatory signals and provide important targets for disrupting the obesity-cancer link. Translational studies involving weight loss interventions in obese women at high risk for breast cancer show good concordance between mouse and human serum markers of energy balance-related hormones (including bioavailable IGF-1) and cytokines, as well as tissue mTOR signaling. We conclude from these transdisciplinary findings that several promising molecular targets (such as mTOR) are emerging for offsetting the procancer effects of obesity. Moreover, preclinical studies of several CR-mimetic agents (such as rapamycin, metformin, and several bioactive food components) provide further proof of the principle that mechanism-based approaches to break the obesity-cancer link by targeting mTOR and/or inflammation are plausible.

Citation Format: Stephen D. Hursting. Obesity, IGF-1 and cancer prevention: Mechanistic insights from transdisciplinary studies. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL05-01.