Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis
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/fl;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. © The Author 2012. Published by Oxford University Press. All rights reserved.
Hudson, Tamaro S.; Carlson, Bradley A.; Hoeneroff, Mark J.; Young, Heather A.; Sordillo, Lorraine; Muller, William J.; Hatfield, Dolph L.; and Green, Jeffrey E., "Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis" (2012). Howard University Cancer Center Faculty Publications. 54.