In this study, we found that a semi-purified, refined AIN93G-based diet with corn oil as sole source of fat augmented the incidences of PCa in our PB-ErbB-2 x Pten+/−
sporadic model of prostate disease from 15% in the lab chow fed mice to 100%. Furthermore reformulation of the AIN93-corn oil diet to incorporate equal amounts of menhaden oil (which has 21% of its triglycerides being n-3 PUFA’s) to corn oil (which has 59% of its triglycerides being n-6 PUFA’s and very little n-3 PUFA’s17
) did not reduce PCa incidences. In addition, cyclin E and p-mTOR were significantly induced in the AIN93-based diets and again the inclusion of fish oil in the diet had no appreciable effect. Therefore, in the context of this preclinical model, we conclude that unrefined chow prevents or delays the onset of PCa while refined AIN93-based diets support prostate epithelial cell cycle progression and tumorigenesis. The availability of dietary n-3 PUFAs did not influence prostate cancer progression in this model.
It is possible that the different outcomes between the current study and those of Burquin et al. may stem in part from the different mouse strains used (FVB vs. C57/Bl6). Also, our animal model retains one pten
allele and supports increased growth factor signaling through ErbB-2, as opposed to PCa driven by deletion of both pten
alleles. Moreover, the previous study relied on purified DHA and EPA as dietary supplements, rather than menhaden oil as the n-3 PUFA source. The previous study’s diet also delivered increased energy from fat (30% vs. 17%, which may independently promote mTOR activation. In studies performed on non-transgenic FVB mice, AIN76-based obesity-inducing diets (containing 60%of calories from fat) induced p-mTOR levels in the prostate as compared to the control diet containing 12%of its calories from corn oil.18
We observed a significant increase in p-mTOR activity in the AIN93-influenced PCa lesions versus chow, however since only 17%of calories in the AIN93G-based diets were derived from fat vs. 13%in chow, it is unlikely that the small increment would affect energy balance sufficiently to independently induce p-mTOR activity. In addition, p-mTOR induction was not observed in the normal epithelium adjacent to the PCa (), nor was it induced in non-transgenic mice fed the refined diets (not shown). We conclude that dietary components present in the unrefined chow protect against PCa perhaps in part through inhibiting unchecked mTOR activation. The loss of these dietary components in the highly refined, westernized AIN93-based diets thereby supports the transformation of the prostate epithelium, but is independent of the PUFA source.
The decrease in the number of cyclin D1-positive cells and the concomitant increase in nuclear cyclin E staining in mice fed the refined diets supports the possibility that the loss of protection against tumorigenesis may be a function of increased cell cycle progression. Changes in p-BAD status were not seen in prostate tumors obtained from mice fed AIN93 diets versus lab chow, suggesting that apoptosis levels may not differ between diets. Additional experiments are underway to assess the levels of apoptosis. Our data raise the possibility that abdominal obesity, levels of activated mTOR and increased nuclear cyclin E positivity may represent biomarkers of dietary influences on PCa progression, especially in at-risk individuals. Interestingly, the refined AIN-93 diets are rich in processed sugars, such as sucrose, while lacking in important plant-derived lignans and isoflavones, and mice fed these diets had larger abdominal fat deposits versus chow, despite maintaining similar overall body weighs. While it is not yet established that the increased visceral fat observed influenced the rate of PCa, these observations suggest that alterations in the metabolic state of the animals may be occurring. Detailed diet reformulation will allow for the investigation into the dietary influences of sugar sources and plant derived compounds not only on PCa but also on energy utilization, metabolism as well as circulating levels of growth factors, insulin and adipokines such as adiponectin and leptin.
The mechanisms of interaction between diet, metabolism and cell cycle progression and tumorigenesis, if they occur, remain to be elucidated. Preclinical studies such as these will be extremely useful in understanding the complex interactions between genes, diet and disease in vivo, and in developing nutritional programs for effective prostate cancer prevention.