Dietary Tomato and Lycopene Modulate Critical Androgen-driven mRNA and miRNA Expression in Early Prostate Carcinogenesis

Background: Epidemiological and laboratory studies suggest tomato and lycopene are dietary anti-cancer agents. Dietary tomato and lycopene have been shown to affect testosterone production and metabolism and vice versa. Testosterone plays critical roles in prostate carcinogenesis by activating the androgen receptor signaling pathway to modulate molecular processes. MicroRNAs (miRNA) are short non-coding RNAs and are deregulated in prostate carcinogenesis. Both diet and testosterone have been shown to target miRNA expression in prostate carcinogenesis. The TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse model develops prostate cancer spontaneously during puberty. We hypothesized that 1) miRNA expression profiles are altered in early TRAMP prostate carcinogenesis, 2) that testosterone status modulates expression of genes in critical pathways and miRNA expression in early prostate carcinogenesis, 3) that consumption of tomato and lycopene leads to altered miRNA and mRNA expression, and 4) that dietary tomato and lycopene play a role in testosterone-driven mRNA and miRNA expression.;Methods: Two, 2x3 factorial studies were designed to investigate the effects of testosterone and tomato carotenoids on murine carcinogenesis gene expression (200 genes) and miRNA expression profile in early prostate carcinogenesis. TRAMP and wild type C57BL/6 mice (4-wk old) were randomly assigned to one of three diets: control, tomato powder, or lycopene beadlets diet.;Results: In wild type mice, plasma lycopene was not detected in control fed mice, and did not differ significantly between tomato or lycopene fed mice ( 0.26 +/- 0.02 vs. 0.27+/- 0.02 mumol/L, P=0.87). Dietary tomato and lycopene did not cause changes of body weight and UGT weight. Castration decreased body weight gain (5.3+/-0.2 vs. 7.0+/-0.3 g), UGT weight (118+/-3 vs. 389+/-10 mg) and prostatic epithelial cell proliferation (0.32+/-0.1 vs. 3.8+/-0.4 %), compared to intact mice (P<0.0001).;Out of 602 miRNAs, 78 were detected in mouse prostatic tissue. Compared to wild type, 41 miRNAs were up-regulated in TRAMP. TRAMP up-regulated miR-21 and miR-15a (8 and 9.23-fold, respectively, P2 fold, P < 0.05) and up-regulated 6 miRNAs (such as miR-150 and miR-1224, -2.94 and -2.11 fold, respectively, P<0.0001). The effect of testosterone-repletion restored miRNAs expression altered by castration to expression levels in intact mice (P<0.001). Moreover, the impact of castration on miRNA expression is genotype specific. Castrated mice had down-regulated miR-200b and miR-15b in TRAMP but not in wild type, compared to intact mice ( P<0.0001).;Conclusion: Castration caused prostate growth regression and inhibition of proliferation in wild type and TRAMP mice. Testosterone status modulated gene expression in cell growth and AhR pathways in early prostate carcinogenesis. Further, dietary tomato and lycopene impacted testosterone-driven AhR signaling-targeted gene expression. The miRNA expression profile was deregulated in TRAMP mice compared to wild type mice in early prostate carcinogenesis. Testosterone was the dominant force regulating miRNA expression, whereas dietary tomato and lycopene play modest roles. Dietary tomato and lycopene independently regulated neuroendocrine biomarkers, a cell adhesion molecule and anti-cancer miRNA expression before causing morphological changes in early prostate carcinogenesis. The current study shows that dietary tomato and lycopene regulated testosterone-driven mRNA and miRNA expression in early prostate carcinogenesis. This supports the previous finding that dietary tomato and lycopene impact testosterone activity. The specific androgen-sensitive mRNA, miRNA, and signaling networks identified may be targets of tomato and lycopene bioactivity in prostate cancer inhibition. (Abstract shortened by UMI.).