In this population-based case-control study, we found that higher toenail selenium levels were not significantly associated with a lower risk of bladder cancer. However, we found evidence of an inverse association among women, moderate smokers, and those with p53 intensely stained tumors.
Several epidemiologic studies have examined the association between selenium and the risk of bladder cancer (5
), and a number of these have observed inverse associations (5
). However, a number of these were relatively small, with only four having >100 cases (5
). One nested case-control study had >100 women cases (5
) and, interestingly, also observed a reduced OR in the highest versus lowest quartile of toenail selenium among women (OR, 0.36; 95% CI, 0.14−0.91) but not men (OR, 1.17; 95% CI, 0.66−2.07; ref. 5
). Our findings also suggest the possibility of a differential association of selenium with the risk of bladder cancer among men and women, although the interaction term was not statistically significant (P
= 0.06). Future research with a larger population of women may help to clarify the association between selenium, gender, and risk of bladder cancer.
Modification of effects by cigarette smoking status has also been observed. Two previous studies found stronger inverse associations between selenium and bladder cancer among past smokers than for never or current smokers, one in women only (5
) and the other for both sexes (7
). In the α-Tocopherol β-Carotene Cancer Prevention Study trial conducted among male smokers, no association was found between selenium and bladder cancer (9
). In our study, we observed a strong inverse relationship between selenium and bladder cancer among those reporting low to moderate levels of smoking, and a similar non-significant trend was observed among nonsmokers. Additionally, we observed an increased risk among heavy smokers in relation to selenium concentrations. In theory, heavy smoking could potentially overwhelm any beneficial effects of selenium on bladder cancer, or worse, act as a promoter of the neoplastic process, analogous to the findings for β-carotene among smokers for lung cancer (16
) or for colorectal adenomas (18
Experimental data indicate potential anticarcinogenic effects of selenium, yet the exact molecular mechanism(s) remains unknown. Selenium is associated with several preventive processes such as reduction of DNA damage, oxidative stress, and inflammation, as well as immune enhancement (4
). Alternatively, there is accumulating evidence that selenium or selenium metabolites may activate genes or modify proteins associated with the p53 pathway, which is frequently altered in human cancers (4
), including a subset of bladder cancers (11
). Selenomethionine has been shown to mediate p53-induced cell cycle arrest and apoptosis in colon cancer cells (21
), whereas selenite seems to enhance superoxide production and apoptosis in human prostate cancer via the p53 pathway (22
). As Luis et al. (11
) describe, p53 alterations (i.e., abnormal staining or mutation) seem to play a central role in bladder carcinomas progressing from carcinoma in situ
/dysplasia to high-grade invasive tumors, but not in the pathway progressing from hyperplasia to low-grade, noninvasive papillary tumors. Albeit speculative, one possibility is that selenium plays a role in the molecular pathogenesis of p53-altered bladder cancers.
One of the limitations of our study is that we did not have the subjects’ prediagnostic toenail selenium levels. This could have affected the results if the disease process changed the selenium levels. However, this possible source of bias is minimized by the use of toenail samples, which likely reflect exposures several months before the date of collection, and by our population-based design that included a large fraction of noninvasive tumors (i.e., less patient morbidity). In conclusion, our results indicate that a higher intake of selenium is not associated with a lower risk of bladder cancer overall. Our findings and others suggest the possibility of selenium affecting subsets of individuals (e.g., women or moderate smokers) or types of tumors (e.g., such as tumors evolving through the p53 pathway).