ER beta shifts from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins

摘要

Both estrogen receptors (ER) alpha (ER alpha) and beta (ER beta) are localized in the nucleus, plasma membrane, and mitochondria, where they mediate the different physiological effects of estrogens. It has been observed that the relative subcellular localization of ERs is altered in several cancer cells. We have demonstrated that MCF-10F cells, the immortal and non-tumorigenic human breast epithelial cells (HBEC) that are ER alpha-negative and ER beta-positive, are transformed in vitro by 17 beta-estradiol (E-2), generating highly invasive cells that are tumorigenic in severe combined immunodeficient mice. E-2-transformed MCF-10F (trMCF) cells exhibit progressive loss of ductulogenesis, invasive (bsMCF) and tumorigenic (caMCF) phenotypes. Immunolocalization of ER beta by confocal fluorescent microscopy and electron microscopy revealed that ER beta is predominantly localized in mitochondria of MCF-10F and trMCF cells. Silencing ER beta expression with ER beta-specific small interference RNA (siRNA-ER beta) markedly diminishes both nuclear and mitochondrial ER beta in MCF-10F cells. The ER beta shifts from its predominant localization in the mitochondria of MCF-10F and trMCF cells to the nucleus of bsMCF cells, becoming predominantly nuclear in caMCF cells. Furthermore, we demonstrated that the mitochondrial ER beta in MCF-10F cells is involved in E-2-induced expression of mitochondrial DNA (mtDNA)-encoded respiratory chain (MRC) proteins. This is the first report of an association of changes in the subcellular localization of ERA with various stages of E-2-induced transformation of HBEC and a functional role of mitochondrial W in mediating E-2-induced MRC protein synthesis. Our findings provide a new insight into one of the potential roles of ERA in human breast cancer. (c) 2007 Elsevier B.V. All rights reserved.