Abstract 3289: Selenium–a possible approach to slow breast cancer metastasis

Abstract

Abstract A major problem with breast cancer is that it tends to metastasize to the skeleton. At the metabolically active area in bones, a vicious cycle forms between breast carcinoma cells, osteoblasts (OBs) and osteoclasts (OCs) which disrupts the functional dynamic balance and usually results in bone loss. The inflammatory response of OBs triggered by breast cancer cells significantly affects the local microenviroment. Some cytokines, such as IL-6, IL-8, and MCP-1 are involved in OC activation and tumor progression. Therefore, it is important to understand the mechanism of induction of OB inflammatory cytokines by breast cancer cells in order to try to decrease the reaction. In previous studies, we found that the key regulator of the inflammatory response of OBs is NF-κB. We also found that methylseleninic acid (MSA), an immediate precursor of methylselenol, (CH3SeH) is capable of inhibiting NF-κB activation and the downstream inflammatory responses. MSA is a commonly used organic selenium compound known to have anti-cancer properties. Sodium selenite is another commonly studied selenium compound. These compounds go through different metabolic pathways and may generate different intermediate metabolites. Therefore, it is important to investigate if the effect of selenium on inflammation is general or is compound and metabolite-specific. Interestingly, our results thus far show that MSA interferes with the OB inflammatory response but the active molecule responsible for the inhibition is short-lived. This finding raises the question of whether a selenoprotein or a metabolite of MSA is the major regulator of the OB inflammatory responses. To address this question, we are investigating the interactions between breast cancer cell conditioned medium and OBs. One well-known NF-κB activator is reactive oxygen species (ROS) which cause intracellular oxidative stress. Some essential anti-oxidant enzymes, including glutathione peroxidase and thioredoxin reductase, are selenoproteins, which explains the protective ability of selenium. We hypothesize that the stimulus from breast cancer cells causes rapid ROS accumulation in OBs and leads to NF-κB activation and downstream cytokine activation. We also hypothesize that by increasing selenium intake, OBs increase their anti-oxidant ability and block NF-κB activation. By using Real-Time PCR, we are evaluating if ROS is being induced by in OBs by breast cancer conditioned medium and asking what ROS metabolic pathway is involved. We will also compare the differences between MSA-supplemented OBs and selenium-deficient OBs. We will silence the expression of selenophosphate synthase 2 (SPS2) to prohibit the production of selenoproteins and investigate if MSA supplementation is still able to block inflammatory responses. If the later is the case, then MSA is active through a metabolite and not a selenoportein. This work was supported by American Institute of Cancer Research (06A027). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3289.