Proteasome-independent down-regulation of estrogen receptor-α (ERα) in breast cancer cells treated with 4,4′-dihydroxy-trans-stilbene

Treatment of cells with estrogens and several pure ER alpha antagonists rapidly induces down-regulation of the alpha-type estrogen receptor (ERa) in the nucleus by mechanisms that are sensitive to the proteasome inhibitors, MG132 and clasto-lactacystin-beta-lactone. Hence, it is believed that these ER ligands induce down-regulation of ER alpha by proteasome-dependent mechanisms, which serve to control both the amount of transcriptional activity and the level of ligand-bound ER alpha in cells. In this study, we observed that treatment of cultured MCF7 and T47D human breast cancer cells with the low affinity ER ligand, 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), inhibited the transcriptional activity of ER alpha and induced slow and gradual decrease in the amount of ER alpha protein (henceforth referred to as down-regulation of ER alpha). The 4,4'-DHS-induced down-regulation of ER alpha in MCF-7 cells involved a mechanism that was insensitive to the two most specific proteasome inhibitors, clasto-lactacystin-plactone and epoxomycin, but sensitive to MG132 at concentrations exceeding that required for maximal inhibition of the proteasome in MCF-7 cells. Therefore, 4,4'-DHS appears to induce down-regulation of ER alpha by a proteasome-independent mechanism. Here, we present data to show that both 4-OH and 4'-OH are critical for the ability of 4,4'-DHS to induce down-regulation of ER alpha and suggest that 4,4'-DHS provides a useful scaffold for development of novel ER alpha antagonists. (c) 2006 Elsevier Inc. All rights reserved.