Dietary Tomato and Lycopene Impact Androgen Signaling- and Carcinogenesis-Related Gene Expression during Early TRAMP Prostate Carcinogenesis

Abstract

Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4-10 wk-of-age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone-repletion (2.5 mg/kg/d initiated 1 wk after castration). Ten-wk-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia (PIN). Of the 200 prostate cancer-related genes measured by quantitative NanoString®, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (P<0.05). In TRAMP, expression of Birc5, Mki67, Aurkb, Ccnb2, Foxm1, and Ccne2 is greater compared to WT and is decreased by castration. In parallel, castration reduces Ki67-positive staining (P<0.0001) compared to intact and testosterone-repleted TRAMP mice. Expression of genes involved in androgen metabolism/signaling pathways are reduced by lycopene feeding (Srd5a1) and by tomato-feeding (Srd5a2, Pxn, and Srebf1). Additionally, tomato-feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, while lycopene-feeding significantly reduced expression of neuroendocrine differentiation-related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early stages of prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk.

Low-lycopene containing tomato powder diet does not protect against prostate cancer in TRAMP mice

“…The mechanism by which TP reduces PCa is unknown; however, lycopene and its metabolites have been hypothesized to alter androgen signaling and synthesis early in PCa development [6]. In this study, we hypothesized that a 10% TP diet initiated at 8 weeks of age when preneoplastic prostatic lesions were present would reduce the incidence of PCa compared with the control diet at 12, 16, and 20 weeks of age.…”

“…In our study, TP diets were consumed after puberty when prostates already had low-and moderate-grade PIN. The TRAMP genotype has been shown to up-regulate genes involved in cell growth and cell-cycle regulation as early as 10 weeks of age [6]. A 10% TP diet initiated at 4 weeks of age and fed until 10 weeks of age also resulted in altered androgen metabolism and signaling [6].…”

“…The TRAMP genotype has been shown to up-regulate genes involved in cell growth and cell-cycle regulation as early as 10 weeks of age [6]. A 10% TP diet initiated at 4 weeks of age and fed until 10 weeks of age also resulted in altered androgen metabolism and signaling [6]. This suggests that early feeding of TP after weaning and before puberty significantly alters prostate-specific androgen metabolism which may impact cancer development.…”

“…Lycopene, the predominant carotenoid found in tomatoes, has been widely investigated for its effects in PCa. Lycopene has been demonstrated to modulate growth factor signaling, cell-cycle programming, angiogenesis, and apoptosis in PCa cell lines [3][4][5][6][7][8][9]. Numerous epidemiology studies have examined the effects of lycopene and tomato products on PCa risk [2, 7,10].…”

“…Other studies began dietary interventions prior to initiation of carcinogenesis or puberty [11][12][13][14]6]. The initiation of a 10% TP diet in TRAMP mice after puberty when prostate-specific pathological changes occur has not been previously investigated.…”