University of Cyprus, Department of Biological Sciences, Lefkosia, Cyprus.
Cancer Lett. 2013 Sep 1;337(2):167-76. doi: 10.1016/j.canlet.2013.05.031. Epub 2013 Jun 7.
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.
这项工作的目的是确定他莫昔芬耐药的分子机制。我们在这里表明，ER-β 在获得他莫昔芬耐药的细胞系（MCF-7/TAM-R）中被表观遗传沉默，这可以通过 5-AZA-脱氧胞苷（5-AZA）和曲古抑菌素-A（TSA）预处理来逆转。随后用 4-羟基他莫昔芬（4-OHT）处理诱导 ER-β 核转位，上调 pS2 和 p21 水平，并降低细胞活力。用 ER-β 表达载体转染使 MCF-7/TAM-R 细胞对 4-OHT 的生长抑制和促凋亡作用敏感，表明 ER-β 的重新表达足以恢复对他莫昔芬的敏感性。这一新发现表明，ER-β 在克服获得性他莫昔芬耐药中是至关重要的，并为针对乳腺癌的新治疗方案提供了思路。
