Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer

Oxidative stress has been postulated as one of the mechanisms underlying the estrogen carcinogenic effect in breast cancel Estrogens are known to increase mitochondrial-derived reactive oxygen species (ROS) by an unknown mechanism. Given that uncoupling proteins (UCPs) are key regulators of mitochondrial energy efficiency and ROS production. our aim was to check the presence and activity of UCPs ill estrogen receptor (ER)-positive and ER-negative breast cancer cells and tumors, as well as their relation to oxidative stress Estrogen (1 nM) induced higher oxidative stress in the ER-positive MCF-7 cell line, showing increased mitochondrial membrane potential, H2O2 levels, and DNA and protein damage compared to ER-negative MDA-MB-231 cells. All isoforms of uncoupling proteins were highly expressed in ER-positive breast cancer cells and tumors compared to negative ones ROS production in mitochondria isolated front MCF-7 was increased by inhibition of UCPs with GDP, but not in mitochondria from MDA-MB-231 Estrogen treatment decreased uncoupling protein and catalase levels in MCF-7 and decreased GDP-dependent ROS production in isolated mitochondria On the whole, these results suggest that estrogens, through all ER-dependent mechanism, play increase mitochondrial ROS production by repressing uncoupling proteins, which offers a new perspective oil the understanding of why estrogens are a risk factor for breast cancer. (C) 2009 Elsevier Inc All rights reserved.