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Treatment of cells with estrogens and several pure ERα antagonists rapidly induces down-regulation of the α-type estrogen receptor (ERα) in the nucleus by mechanisms that are sensitive to the proteasome inhibitors, MG132 and clasto-lactacystin-β-lactone. Hence, it is believed that these ER ligands induce down-regulation of ERα by proteasome-dependent mechanisms, which serve to control both the amount of transcriptional activity and the level of ligand-bound ERα in cells. In this study, we observed that treatment of cultured MCF-7 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 ERα and induced slow and gradual decrease in the amount of ERα protein (henceforth referred to as down-regulation of ERα). The 4,4′-DHS-induced down-regulation of ERα in MCF-7 cells involved a mechanism that was insensitive to the two most specific proteasome inhibitors, clasto-lactacystin-β-lactone 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 ERα 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 ERα and suggest that 4,4′-DHS provides a useful scaffold for development of novel ERα antagonists.