title: Reversal of ER-β silencing by chromatin modifying agents overrides acquired tamoxifen resistance.
abstract: The purpose of this work is to determine the molecular mechanisms underlying tamoxifen resistance. We show here that ER-β is epigenetically silenced in a cell line with acquired tamoxifen resistance (MCF-7/TAM-R) and this could be reversed by 5-AZA-deoxycytidine (5-AZA) and trichostatin-A (TSA) pre-treatment. Subsequent treatment with 4-hydroxy-tamoxifen (4-OHT) induced ER-β nuclear translocation, upregulated pS2 and p21 levels and reduced cell viability. Transfection with an ER-β expression vector sensitized MCF-7/TAM-R cells to the growth inhibitory and pro-apoptotic effects of 4-OHT, indicating that ER-β re-expression alone is sufficient to restore sensitivity to tamoxifen. This novel finding reveals that ER-β is fundamental in overcoming acquired tamoxifen resistance and provides insights for new therapeutic protocols against breast cancer.
authors.affiliation: University of Cyprus, Department of Biological Sciences, Lefkosia, Cyprus.
authors.forename: Chara A
authors.initials: CA
authors.lastname: Pitta
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.forename: Christiana
authors.initials: C
authors.lastname: Charalambous
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Constantinou
mesh_terms: D021581:Active Transport, Cell Nucleus; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D061986:MCF-7 Cells; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047629:Estrogen Receptor beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013629:Tamoxifen; C016601:afimoxifene; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine
keywords: 17β estradiol; 3-(4,5-dimethylthiazol-2-yl)-2,5-monotetrazolium bromide; 4-OHT; 4-hydroxytamoxifen; 5-2′-deoxycytidine; 5-AZA; Breast cancer; DNA methyl transferases; DNMT; E(2); ER-α; ER-β; Epigenetics; Estrogen receptors; HDAC; MTT; SERMs; TSA; Tamoxifen resistance; estrogen receptor α; estrogen receptor β; histone deacetylase; selective estrogen receptor modulators; trichostatin A