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