Intratumoral vitamin D signaling and lethal prostate cancer
Carcinogenesis. 2024 Aug 9:bgae055. doi: 10.1093/carcin/bgae055 PDF behind paywall
Jane B Vaselkiv 1, Irene M Shui 2, Sydney T Grob 1, Caroline I Ericsson 1, Isabel Giovannucci 1, Cheng Peng 1 3, Stephen P Finn 4, Lorelei A Mucci 1 5, Kathryn L Penney 1 3, Konrad H Stopsack 1 6
High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of
- transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, VDR) and
- downregulated genes (CYP24A1, DHCR7).
We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared to tumor-adjacent histologically normal tissue of the same men.
Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest vs. lowest quartile: 0.46, 95% CI: 0.21 to 0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.
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