Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i ⁶ A ⁻ ) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [ C3(1)/Tag ]. The resulting bigenic animals ( i ⁶ A ⁻ / Tag ) and control WT/ Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.

Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented.

The trace element selenium is an essential micronutrient that has received considerable attention for its potential use in the prevention of cancer. In spite of this interest, the mechanism(s) by which selenium might function as a chemopreventive remain to be determined. Considerable experimental evidence indicates that one possible mechanism by which selenium supplementation may exert its benefits is by enhancing the DNA damage repair response, and this includes data obtained using cultured cells, animal models as well as in human clinical studies. In these studies, selenium supplementation has been shown to be beneficial in reducing the frequency of DNA adducts and chromosome breaks, consequentially reducing the likelihood of detrimental mutations that ultimately contribute to carcinogenesis. The benefits of selenium can be envisioned as being due, at least in part, to it being a critical constituent of selenoproteins such as glutathione peroxidases and thioredoxin reductases, proteins that play important roles in antioxidant defence and maintaining the cellular reducing environment. Selenium, therefore, may be protective by preventing DNA damage from occurring as well as by increasing the activity of repair enzymes such as DNA glycosylases and DNA damage repair pathways that involve p53, BRCA1 and Gadd45. An improved understanding of the mechanism of selenium’s impact on DNA repair processes may help to resolve the apparently contradicting data obtained from decades of animal work, human epidemiology and more recently, clinical supplementation studies.

Selenium is effective in reducing cancer incidence in animal models, and epidemiologic data, as well as supplementation trials, have indicated that selenium is likely to be effective in humans. The mechanism by which selenium prevents cancer remains unknown. The mammalian genome encodes 25 selenoprotein genes, each containing one or more molecules of selenium in the form of the amino acid selenocysteine, translationally inserted into the growing peptide in response to the UGA codon. There is evidence that several of these proteins may be involved with the mechanism by which selenium provides its anticancer effects. Data are reviewed indicating that genetic variants of the cytosolic glutathione peroxidase are associated with increased cancer risk, and that loss of one of the copies of this same gene may be involved with malignant progression. Similarly, allelic differences in the gene for a second selenoprotein, Sep15, may be relevant to the protection provided by selenium, and allelic loss at this locus have been reported as well. These data, along with the differential expression patterns reported for other selenoproteins in tumor vs. normal tissues, support the role of selenoproteins in the chemoprotection by selenium.