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.
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.
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