Reversal of ER-β silencing by chromatin modifying agents overrides acquired tamoxifen resistance

• ER-β is silenced in MCF-7 cells with acquired tamoxifen resistance.
• Treatment with the 5-AZA/TSA re-sensitizes cells to the inhibitory effects of 4-OHT.
• Transfection with an ER-β expression vector sensitized resistant cells to 4-OHT.
• ER-β re-expression alone is sufficient to restore sensitivity to tamoxifen.

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.