Abstract A59: Dietary tomato and lycopene inhibition of prostate carcinogenesis in the TRAMP Model is β,β-carotene 9',10'-oxygenase (BCO2)-dependent

Background: Epidemiology and laboratory studies have implicated diets rich in tomatoes and the carotenoid lycopene in prostate cancer risk reduction. However, the specific roles of lycopene, lycopene metabolites, or other tomato phytochemicals are uncertain. The discovery of carotenoid metabolizing enzymes has opened the door to mechanistic studies. The enzyme β,β-carotene 99,109-oxygenase (BCO2) has been shown to asymmetrically cleave lycopene and other carotenoids, yielding metabolites. We hypothesize that these cleavage products may be more biologically active and convey anti-cancer activity. Therefore, we defined the impact of BCO2 ablation on the efficacy of dietary tomato and lycopene to inhibit cancer progression in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse model of prostate carcinogenesis. Methods: BCO2-/- (B6; 129S6-Bcdo2tm1Dnp) mice were crossed with TRAMP+/- (C57BL/6-Tg(TRAMP)8247Ng/J) transgenic mice leading to the generation of TRAMP+/-:BCO2+/+ and TRAMP+/-:BCO2-/-. Male TRAMP:BCO2+/+ and TRAMP:BCO2-/- mice were randomized to three dietary treatments: AIN-93G control diet, 10% tomato powder diet, or 0.25% lycopene beadlet-containing diet from 3 until 18 weeks of age. Serum was collected for carotenoid analysis by HPLC, and prostate tissues were processed for histopathologic assessment of prostate carcinogenesis. Results: TRAMP:BCO2 +/+ mice fed tomato powder and lycopene attained similar serum lycopene concentrations (0.141μM +/- 0.007μM vs. 0.139μM +/- 0.007μM, respectively). The presence of the tomato carotenoids phytofluene (0.13μM +/- 0.002μM) and phytoene (0.025μM +/- 0.003μM) in serum was only observed with tomato feeding as anticipated. Loss of BCO2 enzyme resulted in significantly increased serum concentrations of total, total cis, 5-cis, and all-trans lycopene in both tomato and lycopene fed mice, and the accumulation of phytoene, phytofluene, and zeta-carotene in the tomato fed mice compared to the BCO2+/+ counterparts. For example, total serum lycopene levels were 0.229μM +/- 0.029μM and 0.223μM +/- 0.030μM in tomato- and lycopene-fed TRAMP:BCO2-/- mice, respectively. Dietary tomato powder and lycopene inhibited cancer progression. Incidence of cancer was 80% in control diet-fed TRAMP:BCO2+/+ mice, while tomato and lycopene feeding decreased incidence to 15% and 11%, respectively. Ablation of BCO2 (TRAMP:BCO2-/-) partially attenuated the anti-cancer efficacy of tomato and lycopene observed in TRAMP:BCO2+/+ mice as the incidence was 24% for tomato-fed and 46% for lycopene-fed mice. Conclusions: Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a BCO2-dependent manner. Future human studies to examine the role of lycopene metabolism and BCO2 genotype in cancer risk reduction are warranted. Citation Format: Hsueh-Li Tan, Jennifer M. Thomas-Ahner, Nancy E. Moran, Gregory S. Young, John W. Erdman, Jr., Steven K. Clinton. Dietary tomato and lycopene inhibition of prostate carcinogenesis in the TRAMP Model is β,β-carotene 99,109-oxygenase (BCO2)-dependent. [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 A59.