Selenium is an essential
micronutrient in the diet of humans and other mammals. Based largely on animal studies and epidemiological evidence,
selenium is purported to be a promising
cancer chemopreventive agent. However, the
biological mechanisms by which chemopreventive activity takes place are poorly understood. It remains unclear whether
selenium acts in its elemental form, through incorporation into organic compounds, through
selenoproteins or any combination of these. The purpose of this study was to determine whether
selenoproteins mitigate the risk of developing chemically induced
mammary cancer.
Selenoprotein expression was ablated in mouse mammary epithelial cells through genetic deletion of the
selenocysteine (Sec)
tRNA gene (Trsp), whose product, designated
selenocysteine tRNA, is required for
selenoprotein translation. Trsp floxed and mouse mammary tumor virus (MMTV)-cre mice were crossed to achieve tissue-specific excision of Trsp in targeted mammary glands. Eight- to twelve-week-old second generation Trsp(fl/+);wt, Trsp(fl/+);MMTV-cre, Trsp(fl/fl);wt and Trsp(fl/fl);MMTV-cre female mice were administered standard doses of the
carcinogen, 7,12-dimethylbenzylbenz[a]antracene. Our results revealed that heterozygous, Trsp(fl/+);MMTV-cre mice showed no difference in
tumor incidence,
tumor rate and survival compared with the Trsp(fl/+);wt mice. However, 54.8% of homozygous Trsp(fl/f)(l);MMTV-cre mice developed mammary
tumors and exhibited significantly shorter survival than the corresponding Trsp(fl/fl);wt mice, where only 36.4% developed
tumors. Loss of the homozygous Trsp alleles was associated with the reduction of
selenoprotein expression. The results suggest that mice with reduced
selenoprotein expression have increased susceptibility to developing
carcinogen-induced mammary
tumors and that a major protective mechanism against
carcinogen-induced
mammary cancer requires the expression of these
selenoproteins.