title: Proteasome-independent down-regulation of estrogen receptor-alpha (ERalpha) in breast cancer cells treated with 4,4'-dihydroxy-trans-stilbene.
abstract: 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.
authors.affiliation: Department of Pediatrics, Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Suite 3100, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Kannan V
authors.initials: KV
authors.lastname: Balan
authors.forename: Yongbao
authors.initials: Y
authors.lastname: Wang
authors.forename: Siming W
authors.initials: SW
authors.lastname: Chen
authors.forename: Jin-Chun
authors.initials: JC
authors.lastname: Chen
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Zhong-Li
authors.initials: ZL
authors.lastname: Liu
authors.forename: Panayotis
authors.initials: P
authors.lastname: Pantazis
authors.forename: James H
authors.initials: JH
authors.lastname: Wyche
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Han
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D047628:Estrogen Receptor alpha; D013267:Stilbenes; D004958:Estradiol; C010118:4,4'-dihydroxystilbene; D046988:Proteasome Endopeptidase Complex