ARTICLE ABSTRACTThe hypothesis that dietary tomato consumption or the intake of the carotenoid lycopene inhibits prostate cancer arose from epidemiologic studies and is supported by preclinical rodent experiments and in vitro mechanistic studies. We hypothesize that variation in activity of carotenoid cleavage enzymes, such as β-carotene 9′,10′-oxygenase (BCO2), may alter the impact of dietary tomato and lycopene on prostate carcinogenesis and therefore examined this relationship in the TRAMP model. Starting at 3 weeks of age, TRAMP:Bco2+/+ and TRAMP:Bco2−/− mice were fed either AIN-93G control, or semipurified diets containing 10% tomato powder or 0.25% lycopene beadlets until 18 weeks of age. Both tomato- and lycopene-fed TRAMP:Bco2−/− mice had significantly greater serum concentrations of total, 5-cis, other cis, and all-trans lycopene than TRAMP:Bco2+/+ mice. Tomato- and lycopene-fed mice had a lower incidence of prostate cancer compared with the control-fed mice. Although Bco2 genotype alone did not significantly change prostate cancer outcome in the control AIN-93G-fed mice, the abilities of lycopene and tomato feeding to inhibit prostate carcinogenesis were significantly attenuated by the loss of Bco2 (Pinteraction = 0.0004 and 0.0383, respectively). Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a Bco2 genotype-specific manner, potentially implicating the anticancer activity of lycopene cleavage products. This study suggests that genetic variables impacting carotenoid metabolism and accumulation can impact anticancer activity and that future efforts devoted to understanding the interface between tomato carotenoid intake, host genetics, and metabolism will be necessary to clearly elucidate their interactive roles in human prostate carcinogenesis. Cancer Prev Res; 10(2); 161–9. ©2016 AACR.