The Role of Estrogen Receptors in Breast Cancer Targeted Therapeutics and Chemoprevention

Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen have found applications in the control and treatment of breast cancer. However, one major issue in breast cancer therapeutics is the acquisition of drug resistance through drug-induced selection of cancer cells not expressing the drug target (in this case the ER). This is the result of eithergenetic (mutations) or epigenetic events. For addressing this issue we used an MCF-7 breast cancer cell line with acquired tamoxifen resistance. We found that the estrogen receptor (ER)-β is epigenetically silenced due to long-term treatment with 4-hydroxy-tamoxifen (4-OHT). Suppression of ER-β expression was reversed upon treatment with either the demethylating agent 5-aza-dc-deoxycytidine (5-aza-dc) or the histone deacetylase inhibitor trichostatin-A (TSA), and this reversal was even more prevalent with their combination. 4-OHT induced nuclear translocation of the re-expressed ER-β and transcriptional activation of pS2 and p21, indicating that the receptor is functional. Importantly, transfection of MCF-7/TAM-R cells with an ER-β expression vector, sensitized cells to the growth inhibitory and pro-apoptotic effects of 4-OHT, indicating that ER-β reexpression is sufficient to restore sensitivity to 4-OHT. These results strongly support that silencing of ER-β expression is coupled to acquired tamoxifen resistance. Therefore, ER-β is a “good” prognostic marker and strategies aiming to reexpress this receptor could find applications in targeted therapeutics (or precision medicine) and cancer chemoprevention.