| Summary: | The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing <i>TMPRSS2-ERG</i> (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case–control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both <i>TMPRSS2-ERG</i> (fusion)-driven (with conditional deletion of <i>Pten</i>) and non-<i>TMPRSS2-ERG</i>-driven (Hi-Myc<sup>+/−</sup> mice) PCa. Male mice (<i>n</i> = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc<sup>+/−</sup> mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the <i>TMPRSS2-ERG</i> (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79–91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc<sup>+/−</sup> mice, suggesting that NSAIDs exert a specific protective effect against <i>TMPRSS2-ERG</i> (fusion)-driven PCa.
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