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Proteasome-independent down-regulation of estrogen receptor-alpha (ERalpha) in breast cancer cells treated with 4,4'-dihydroxy-trans-stilbene.

Balan KV, Wang Y, Chen SW, Chen JC, Zheng LF, Yang L, Liu ZL, Pantazis P, Wyche JH, Han Z

Department of Pediatrics, Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Suite 3100, Case Western Reserve University, Cleveland, OH 44106, USA.

Treatment of cells with estrogens and several pure ERalpha antagonists rapidly induces down-regulation of the alpha-type estrogen receptor (ERalpha) 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 ERalpha by proteasome-dependent mechanisms, which serve to control both the amount of transcriptional activity and the level of ligand-bound ERalpha 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 ERalpha and induced slow and gradual decrease in the amount of ERalpha protein (henceforth referred to as down-regulation of ERalpha). The 4,4'-DHS-induced down-regulation of ERalpha in MCF-7 cells involved a mechanism that was insensitive to the two most specific proteasome inhibitors, clasto-lactacystin-beta-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 ERalpha 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 ERalpha and suggest that 4,4'-DHS provides a useful scaffold for development of novel ERalpha antagonists.

Published 9 August 2006 in Biochem Pharmacol, 72(5): 573-81.
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