Methylseleninic acid (MSA) inhibits 17β-estradiol-induced cell growth in breast cancer T47D cells via enhancement of the antioxidative thioredoxin/thioredoxin reductase system

The purpose of this study was to clarify the cell growth inhibitory mechanism of human breast cancer cells caused by selenium (Se) compounds. In the presence of 17 beta-estradiol (E-2) at physiological concentrations, growth of estrogen receptor alpha (ER alpha)-positive T47D cells was markedly inhibited by 1 x 10(-6) mol/L methylseleninic acid (MSA) with no Se related toxicity. Under conditions where cell growth was inhibited, MSA decreased ER alpha mRNA levels and subsequent protein levels; further decreasing expression of estrogen-responsive finger protein (Efp) which is a target gene product of ER alpha and promotes G2/M progression of the cell cycle. Therefore, the decline in Efp expression is presumed to be involved in G2 arrest. Coincidentally, the antioxidative thioredoxin/thioredoxin reductase (Trx/TrxR) system in cells was enhanced by the synergistic action of E-2 and MSA. It has been reported that ROS-induced oxidative stress enhanced ER alpha expression. E-2 increased production of intracellular ROS in T47D cells. Meanwhile, MSA significantly decreased E-2-induced ROS accumulation. From these results, activation of the Trx/TrxR system induced by the coexistence of MSA and E-2 suppresses oxidative stress and decreases expression of ER alpha, and finally induces the growth arrest of T47D cells through disruption of ER alpha signaling.