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Ljepoja, Bojan; Garcia-Roman, Jonathan; Sommer, Ann-Katrin; Wagner, Ernst; Roidl, Andreas (2019): MiRNA-27a sensitizes breast cancer cells to treatment with Selective Estrogen Receptor Modulators. In: Breast, Vol. 43: pp. 31-38
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Background: MicroRNA-27a (miR-27a) is a small non-coding RNA, shown to play a role in multiple cancers, including the regulation of ER alpha expression in breast cancer. Most ER alpha positive tumors are treated with Selective Estrogen Receptor Modulators (SERMs) and thus the role of miR-27a expression in response to SERM treatment is of interest. Methods: Tamoxifen resistant cells were generated by molecular evolution with six cycles of tamoxifen treatment. MCF7 and T47D luminal A breast cancer cell lines were either treated with miR-27a mimics, or ER-signaling was modulated ectopically. The changes were analyzed with RT-qPCR, western blotting and transcriptional activity ERE-reporter assays. Moreover, the response to SERM treatments (tamoxifen, endoxifen and toremifen) was investigated by cell viability and apoptosis measurements. An in silico analysis of survival data from the METABRIC study was performed in order to assess the prognostic value of miR-27a for response to SERM treatment. Results: Tamoxifen-resistant cells showed decreased expression of ER alpha and miR-27a. The overexpression of miR-27a increased the levels of ER alpha, while modulation of ER alpha decreased miR-27a expression. High miR-27a expression increased the sensitivity of MCF7 and T47D cells to SERM treatments and resensitized the cells to tamoxifen. Patient survival of luminal A breast cancer patients that underwent endocrine therapies was better in groups with high miR-27a expression. Conclusion: MiR-27a sensitizes luminal A breast cancer cells to SERM treatments based on a positive feedback loop with ER alpha. An increased overall-survival of ER-positive breast cancer patients that underwent endocrine treatments and displayed high miR-27a levels was found. (C) 2018 Elsevier Ltd. All rights reserved.