The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor α-negative breast cancer cells to tamoxifen
The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor α-negative breast cancer cells to tamoxifen
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DOI：
10.1038/sj.onc.1207315
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发表时间：
2004-03-04
期刊：
影响因子：
8
通讯作者：
Lee, JS
中科院分区：
文献类型：
--
作者：
Jang, ER;Lim, SJ;Lee, JS
许多乳腺癌病例显示雌激素受体（ER）α表达的丧失，这导致对抗激素治疗无反应，即使没有结构和生物化学相似的ER β的丧失。ER活性受到转录调节因子如组蛋白脱乙酰酶（HDAC）的正调控和负调控，已知组蛋白脱乙酰酶是负ER调节因子。在这里，我们评估了使用ER β作为他莫昔芬治疗的替代靶点，通过用HDAC抑制剂曲马斯他汀A（TSA）治疗ER α阴性，β阳性乳腺癌细胞，并测试ER β上调后他莫昔芬反应性是否增加。TSA增强了这些细胞中的总体ER转录活性，如通过雌激素反应元件调节的报告基因和孕酮受体（一种已知的ER靶点）的表达所观察到的，而没有ER α恢复。此外，TSA诱导ER β而非α的表达和核转位，表明这些导致ER转录活性增加的作用是通过ER β而非α介导的。此外，在用TSA治疗后，以前无反应的MDA-MB-231和Hs 578 T乳腺癌细胞变得对他莫昔芬有反应。然而，通过短干扰RNA减少ER β的表达消除了TSA在这些细胞中诱导的致敏作用。总之，这些结果表明HDAC抑制剂TSA可能通过上调ER β活性使ER α阴性、抗肿瘤药无反应的乳腺癌细胞对他莫昔芬治疗敏感。
Many cases of breast cancer show loss of estrogen receptor (ER) alpha expression, which leads to unresponsiveness to antihormonal treatment even though there is no loss of the structurally and biochemically similar ER beta. ER activity is positively and negatively regulated by transcriptional regulators such as histone deacetylase (HDAC), which is known to be a negative ER regulator. Here, we evaluated using ER beta as an alternative target for tamoxifen therapy by treating ER alpha-negative, beta-positive breast cancer cells with the HDAC inhibitor trichostatin A (TSA), and testing whether tamoxifen responsiveness increased following upregulation of ER beta. TSA enhanced the overall ER transcriptional activity in these cells, as visualized by estrogen response element-regulated reporter and the expression of progesterone receptor, a known ER target, without ER alpha restoration. Additionally, TSA induced the expression and nuclear translocation of ER beta but not alpha, suggesting that these actions leading to increase of ER transcriptional activity are mediated through ER beta rather than alpha. Furthermore, following treatment with TSA, the formerly unresponsive MDA-MB-231 and Hs578T breast cancer cells became responsive to tamoxifen. However, reduction of ER beta expression by short interfering RNA abrogated this TSA-induced sensitization effect in these cells. Together, these results show that the HDAC inhibitor TSA sensitized ER alpha-negative, antihormone-unresponsive breast cancer cells to tamoxifen treatment possibly by upregulating ER beta activity.