Science peels the onion of selenium effects on prostate carcinogenesis.

The role of the essential trace element selenium in prostate cancer was first (and last) editorialized in the Journal in 1998 in conjunction with the report of the first large prospective observational study of selenium and the risk of advanced prostate cancer (1,2). Although the principals for the 1998 study were the same as those for the observational study by Li et al. (3) in this issue of the Journal, much has changed in the basic scientific understanding of selenium. The onion, an allium vegetable that concentrates selenium, is an apt metaphor for the scientific work of peeling back the layers of molecular effects and mechanisms underlying the strong selenium epidemiology in the prostate. The past 6 years have seen the publication of seven prospective epidemiologic studies of selenium status and prostate cancer (including the study in this issue of the Journal) (2–8), with a collective total of nearly 2000 case subjects. The studies involved low [Europe (8)], moderate [Maryland (5)], and high [Hawaii (4)] selenium status populations, and all but one found a protective effect associated with higher concentrations of selenium. Furthermore, low plasma selenium levels are associated with increases in other cancers and human diseases (9). Although the findings of the observational studies have been encouraging and consistent regarding the prostate, the most powerful evidence to date for the beneficial effect of selenium is the 49% reduction in prostate cancer incidence in the randomized, placebo-controlled Nutritional Prevention of Cancer (NPC) trial, in which selenium was administered at 200 g/day (10,11). On the basis of the NPC trial, epidemiologic studies, a randomized prevention trial in China of selenium in combination with other minerals and vitamins (12), and early preclinical data (13–17) available in 2000, selenium was included in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in 32 400 men to definitively test the role of supplementation with selenium and/or vitamin E in the prevention of prostate cancer (18). Before addressing the basic science behind the results of these selenium studies, we will highlight two important aspects of the study by Li et al. (3): selenium effects by stage of disease and selenium effects by baseline prostate-specific antigen (PSA) levels. The finding that selenium was associated with a reduced risk of advanced prostate cancer (stage C or D) is consistent with the findings of three of four other epidemiologic studies (2–4) that assessed this variable and supports the hypothesis of Li et al.—that selenium affects tumor progression rather than premalignancy. This finding also is consistent with the observation that selenium was associated with a greater reduction in risk for men with PSA levels of greater than 4 ng/mL than for men with PSA levels of 4 ng/mL or less. These stage and PSA associations seemingly are at odds, however, with the NPC findings that the protection conferred by selenium was largely due to reduced local disease and was limited almost exclusively to men with PSA levels of 4 ng/mL or less (11). The discrepancy between the results of Li et al. (3) and those of the NPC may be due, in part, to differences in study designs (i.e., observation versus intervention) and to enormous differences in the doses and durations of exposure that were assessed. Although associated with lower PSA levels, the risk reduction in the NPC study does not necessarily conflict with the hypothesis of Li et al. (3) that selenium slows tumor progression (3). First, the curves of prostate cancer incidence for the placebo and selenium arms separated early in the NPC study, which would not be expected for effects on the decades-long process of premalignant tissue transforming into malignant tissue. Second, prostate cancer is far more prevalent in men with lower PSA levels than is generally thought. Thompson et al. (19) recently reported that the prevalence of prostate cancer (detected by biopsy after 7 years of close follow-up) was surprisingly high at 15% among 3820 men with PSA levels of 4.0 ng/mL or less on the placebo arm of the Prostate Cancer Prevention Trial (PCPT). This rate begins to approach that reported heretofore for men with PSA levels of 4–10 ng/mL (20), suggesting that future exploratory analyses probably should set the PSA cut point substantially below 4 ng/mL. Therefore, the NPC result may have been based on slowing or halting the progression of microscopic, subclinical prostate cancer. Moreover, transformation was likely prevented or delayed, as suggested by the durability of the separation of the prostate cancer curves. This important issue of preventing or delaying transformation to cancer versus treating subclinical, microscopic cancer has been debated since publication of the primary reports of other large-scale trials, including the PCPT (19,21,22). In either case, the effect of selenium would be beneficial. Molecular and cellular bases for the published observations of selenium preventive activity in the prostate are emerging and providing biologic plausibility for clinical prostate cancer prevention trials of selenium, such as the SELECT. The primary nutritional role of selenium in regulating the redox state and energy metabolism involves its incorporation as selenocysteine, the 21 amino acid, into selenoproteins. Selenium potentially affects cancer development through its known effects on oxidative stress, DNA repair, inflammation, apoptosis, proliferation, carcinogen metabolism, testosterone production, angiogenesis, fat metabolism, and immune function (9,23–25). The potential for these effects in the prostate is supported by data showing that