Abstract LB-079: Effect of diet-induced obesity on tobacco carcinogen-induced lung carcinogenesis in mice

Obesity has been shown to increase breast cancer risk by causing inflammation through altered estrogen signaling. Whether obesity plays a similar role in lung carcinogenesis is currently not known. However, the role of estrogen signaling in the development and progression of lung cancer is well-established and the inflammation-estrogen signaling axis may underlie the link between obesity and lung cancer risk as well. We used a preclinical animal model to determine the role of diet-induced obesity in promoting lung carcinogenesis and inflammation caused by tobacco carcinogen exposure [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNK] and the ability of estrogen pathway and/or inflammatory inhibitors to reduce this effect. Female FVB/N mice were administered a high fat (HF; 60kcal% fat; N = 67) or low fat (LF; 10kcal% fat; N = 66) diet ad libitum starting 2 weeks before NNK exposure until sacrifice. NNK was administered for 4 weeks, followed by a 4 week holding period for preneoplasia development. Subsequently, placebo, the aromatase inhibitor anastrozole (0.1mg/kg; p.o. daily) and/or aspirin (25mg/kg; p.o. daily) treatment was administered for 13 weeks after which lung tumors and blood biomarkers were evaluated. Poisson regression was used to assess differences in tumor number and mixed-effects models for differences in tumor size. Overall, the LF diet resulted in more tumors per animal (HF mean number of tumors 8.8, range 1-16; LF mean number of tumors 11.5, range 5-20), but signficantly larger tumors were observed in the HF fed mice compared to LF fed mice in all four treatment groups (HF mean tumor size 0.60 mm2, range 0.05-12.24 mm2; LF mean tumor size 0.37 mm2, range 0.06-2.14 mm2) which correlated with increased tumor Ki67 expression. Anastrozole and aspirin as single agents were significantly more effective at decreasing tumor number in HF fed mice compared to LF fed mice; however, the combined treatment was equally effective in both dietary groups. Inflammatory cell count in bronchoalveolar lavage fluid, tumor infiltrating inflammatory cells and tumor aromatase, COX-2 and nuclear factor kappa-B expression were all increased in HF compared to LF fed mice. This increased inflammatory response may be responsible for the observed increase in tumor size in the HF fed mice. In addition, levels of circulating inflammatory cytokines such as IL-6, IL-10 and TNF-α were significantly down-modulated by anastrozole and also by combined treatment in LF fed mic