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Research Project: Nutritional Role of Phytochemicals

Location: Children's Nutrition Research Center

Title: Beta-carotene oxygenase 2 genotype modulates the impact of dietary lycopene on gene expression during early TRAMP prostate carcinogenesis

item MORAN, NANCY - Children'S Nutrition Research Center (CNRC)
item THOMAS-AHNER, JENNIFER - The Ohio State University
item SMITH, JOSHUA - University Of Illinois
item SILVA, CEASAR - Children'S Nutrition Research Center (CNRC)
item HASON, NOOR - Children'S Nutrition Research Center (CNRC)
item ERDMAN, JOHN - University Of Illinois
item CLINTON, STEVEN - The Ohio State University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2021
Publication Date: 12/29/2021
Citation: Moran, N.E., Thomas-Ahner, J.M., Smith, J.W., Silva, C., Hason, N.A., Erdman, J.W., Clinton, S.K. 2021. Beta-carotene oxygenase 2 genotype modulates the impact of dietary lycopene on gene expression during early TRAMP prostate carcinogenesis. Journal of Nutrition. 152(4):950-960.

Interpretive Summary: Population studies in humans have shown that consuming tomato and lycopene, the red carotenoid in tomatoes, is associated with lower risk of prostate cancer. Studies in mice have shown that lifelong consumption of tomato and lycopene does indeed disrupt prostate cancer processes and result in a lower incidence of prostate cancer. Both mice and humans have an enzyme, called beta-carotene oxygenase 2 (BCO2) that breaks down carotenoids including lycopene, and may be an important mediator of lycopene’s prevention of prostate cancer. This study found that even in early life, in the earliest stages of prostate tumorigenesis, gene expression in the prostate differed in mice fed tomato or lycopene, versus control diets. Further, the pattern of prostate gene expression differed in lycopene-fed mice depending on whether or not Bco2 was expressed. Expression of genes related to carcinogenesis and to lipid metabolism differed by diet and Bco2 genotype. These findings shed light on how diet can modulate early prostate carcinogenesis.

Technical Abstract: 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.