Vitamin D in Blood and Risk of Prostate Cancer: Lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial

Abstract

The effects of blood levels of 25-hydroxyvitamin D (25-OHD) on the risk of total, low-, and high-grade prostate cancer were examined in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT). In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent "U"-shaped effect in other men. The "U-shaped" curve may reflect detection bias. In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers. The results from these large prevention trials support the hypothesis that circulating levels of 25-OHD decrease the risk of clinically relevant prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1447-9. Ó2014 AACR.The hypothesis that vitamin D, or its major source, sunlight, inhibits prostate cancer has gone from a "dark horse" to a front-runner in the race to understand the epidemiology of prostate cancer. Clinically relevant prostate cancer preferentially afflicts the elderly, Blacks, and residents in northern latitudes (1). Conversely, the prevalence of subclinical prostate cancer (cancer detected in asymptomatic men) increases with age but does not vary by race or geography. In 1990, Schwartz and Hulka noted that the major descriptive risk factors for clinical prostate cancer (age, race, and northern latitudes) are associated with vitamin D deficiency and hypothesized that vitamin D inhibits the development of clinical prostate cancer from the ubiquitous subclinical cancers (2). Bolstered by maps showing that the geographic distribution of prostate cancer mortality is inversely correlated with the geographic distribution of sunlight (3), the hypothesis that vitamin D inhibits prostate cancer galvanized research in many fields. In the laboratory, it ceased to be a hypothesis, as we learned that prostate cells possess the receptor for the vitamin D hormone, 1,25-dihydroxyvitamin D (discovered in 1992; ref. 4), and the enzyme 1a-hydroxylase, which converts the vitamin D pro-hormone, 25-hydroxyvitamin D (25-OHD), into the vitamin D hormone (discovered in 1998; ref. 5). Both the hormone and pro-hormone exert prodifferentiating, antiproliferative, and antimetastatic effects on prostate cells (for reviews see refs. 6-8).Although the results of experimental studies of vitamin D and prostate cancer have been uniformly positive, the results of observational studies have been mixed. Numerous ecologic studies replicated the inverse correlation of prostate cancer rates with sunlight (9-11). Analytic studies support a protective effect of sunlight exposure in individual men, including an effect for exposure during early life (12-14). However, results from serologic studies of 25-OHD and prostate cancer risk have been inconsistent, with articles reporting negative, null, and positive associations (for review see ref. 15). This inconsistency has several causes. Fir...

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

“…The SELECT trial found no decrease in PCa risk in the selenium supplement treated group and a statistically insignificant increase in PCa risk with vitamin E [23]. A silver lining in this study was the finding that PCa incidence decreased with respect to a linear increase in 25-hydroxy vitamin D in circulation of the patients enrolled in the study [24]. …”

Vitamin D and Colorectal, Breast, and Prostate Cancers: A Review of the Epidemiological Evidence

“…To date, several studies have reported a significant inverse association between 25(OH)D and more advanced prostate cancers 89 , 91 , 94 , which might suggest that vitamin D has an inhibitory effect on prostate cancer progression and/or that it may be critical in the carcinogenesis pathway from which clinically relevant, but not less aggressive, cancers arise 97 . However, other investigations have failed to show such a relationship 82 , 85 , 95 , or have even demonstrated a significantly increased risk for aggressive prostate cancer with higher levels of 25(OH)D 83 , 84 , 88 .…”

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“…The primary active form of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol) aids in proper bone formation, induces differentiation of some immune cells, and inhibits pro-tumor pathways, such as proliferation and angiogenesis, and has been suggested to benefit PCa risk [ 100 ]; however, findings continue to be inconclusive. More recent studies found that increased serum vitamin D levels were associated with decreased PCa risk [ 101 , 102 ]. Further, supplementing vitamin D may slow PCa progression or induce apoptosis in PCa cells [ 103 - 105 ].…”