Raloxifene (RLX), a selective estrogen receptor modulator (SERM), binds to the estrogen receptor alpha (ER alpha) and acts as an agonist in some tissues, and as an antagonist in others. To clarify the molecular mechanism underlying the tissue specificity of SERMs, we examined the intracellular localization of ER alpha using a green fluorescent protein (GFP)-tagged protein in culture cells from various tissues. Although ER alpha formed intranuclear foci in the presence of estradiol (E(2)). RLX translocated ER alpha into the nucleoli in breast cancer cell lines This phenomenon was not observed in cells from other tissues. Immunofluorescence staining revealed that endogenous ER alpha was also translocated into the nucleoli in the presence of RLX Mutation analyses demonstrate that helix 12 of ER alpha is essential to the nucleolar translocation of ER alpha These results suggest that translocation of ER alpha into the nucleoli is RLX-specific and is a key event for RLX-induced growth repression of mammary gland cells (C) 2010 Elsevier Ireland Ltd All rights reserved.