The role of selenoproteins in mammary tumorigenesis: A potential mechanism for the chemopreventive effects of selenium. Free

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Selenium (Se) is an essential micronutrient in the diet of mammals and humans and is often found in many vegetables and grains grown in selenium-rich soil. Based upon recent epidemiological evidence, selenium is considered to be a promising chemopreventive agent and is being studied in the large and expensive SELECT trial. However, the biological mechanisms of selenium action in chemoprevention is poorly understood. In this regard, it is not known whether selenium acts in elemental form, through its incorporation into organic compounds, or through it being a component of selenoproteins. Selenium is incorporated into protein by way of the selenocysteinyl-tRNA that recognizes the specific UGA codons in mRNA. The biosynthetic mechanism of selenoprotein production can be altered to examine the role of Se-proteins in cancer progression by genetically altering the Sec-tRNA. The purpose of this study is to determine whether selenoproteins play a role in preventing breast cancer. We have generated mice in which sec-tRNA is haplo-insufficient specifically in mammary glands that are induced to form tumors by exposure to the carcinogen 7,12-dimethylbenzylbenz[a]antracene (DMBA). Tissue-specific excision of Sec-tRNA in the mammary was achieved using MMTV-cre mice to remove a floxed Sec-tRNA allele in the mammary glands. Thirty three 8-12 week old female Sec-tRNAfl/+;cre- and sixty Sec-tRNAfl/+;cre+ mice in the same genetic background were administered DMBA. No significant differences in body weights between the sec-tRNA knockout and control groups were observed. Gross clinical and histologic examiniation confirms that to date 32% of the Sec-tRNAfl/+;cre+ mice develop mammary adenosquamous carcinomas, whereas only 9% of the control Sec-tRNAfl/+;cre- mice develop tumors. These preliminary results suggest that mice with reduced Sec-tRNA are highly susceptible to developing carcinogen-induced mammary tumors, presumably through the action of selenoproteins. The role of cre recombinase in carcinogen-induced tumorigenesis is also being determined.