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Background: Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. Methods: We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. Results: In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR &amp;lt;0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. Conclusions: These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. Impact: Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.

Gene Expression Pathways in Prostate Tissue Associated with Vigorous Physical Activity in Prostate Cancer