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β-carotene Oxygenase 2 Genotype Modulates the Impact of Dietary Lycopene On Gene Expression During Early TRAMP Prostate Carcinogenesis.

BACKGROUND
Epidemiologic studies suggests lycopene and tomato intake are inversely associated with human prostate cancer incidence. Genetically-driven murine prostate carcinogenesis (TRAMP model) is inhibited by lycopene- or tomato-feeding, and these effects are modulated by beta-carotene oxygenase 2 (Bco2) genotype.


OBJECTIVES
We seek insight into this interaction through evaluation of prostate gene expression patterns during early TRAMP carcinogenesis.


METHODS
Three-week-old TRAMP/+ or TRAMP/- x Bco2+/+ or Bco2-/- mice were fed a control, lycopene beadlet, or 10% tomato powder-containing semi-purified diet (providing 0, 384 and 462 mg lycopene/kg diet, respectively) for 5 weeks. Gene expression patterns were evaluated by prostate cancer- and cholesterol and lipoprotein metabolism-focused arrays at 8 weeks-of-age.


RESULTS
TRAMP genotype profoundly alters gene expression patterns, specifically inducing pathways associated with cell survival (z-score = 2.09, -log(P-value) = 29.2), p53 signaling (z-score 1.13, -log(P-value) = 13.5), and PI3K/AKT signaling (z-score = 0.302, -log(P-value) = 12.1), while repressing PTEN signaling (z-score = -0.905, -log(P-value) = 12.3), cholesterol synthesis (z-score = -1.941, -log(P-value) = 26.2), and LXR/RXR pathway activation (z-score = -1.941, -log(P-value) = 23.1). In comparison, lycopene- and tomato-feeding modestly modulate strong procarcinogenic TRAMP signaling. Lycopene decreased gene expression related to carcinogenesis (Nkx3-1), tomato feeding increased expression of a gene involved in circadian regulation (Arntl), and tomato and/or lycopene increased expression of genes involved in lipid metabolism (Fasn, Acaca, Srebf1, Hmgcr, and Ptgs1) (all P < 0.05). The impact of Bco2 genotype was limited to a subset of lycopene-impacted genes (Apc, Mto1, Nfkb1, and Rbm39).


CONCLUSIONS
The TRAMP genotype strongly impacts procarcinogenic gene expression prior to emergence of histopathologic disease. Dietary tomato and lycopene modestly temper these processes, while Bco2 genotype has a limited impact at this early stage. These observed patterns provide insight into the complex interactions between a dietary variable, here tomatoes and lycopene, genes impacting nutrient metabolism, and their modulating influences on oncogene-driven prostate carcinogenesis. These findings provide further mechanistic support, consistent with cancer outcomes in rodents experiments and human epidemiologic studies.