Corresponding Author: Gauri J. Sabnis, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 685 W. Baltimore St, HSF-I 580, Baltimore, MD 21201.
Mol Cancer Ther. 2013 Dec;12(12):2804-16. doi: 10.1158/1535-7163.MCT-13-0345. Epub 2013 Oct 3.
We previously showed that in innately resistant tumors, silencing of the estrogen receptor (ER) could be reversed by treatment with a histone deacetylase (HDAC) inhibitor, entinostat. Tumors were then responsive to aromatase inhibitor (AI) letrozole. Here, we investigated whether ER in the acquired letrozole-resistant tumors could be restored with entinostat. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ(4)A), the aromatizable substrate. When the tumors reached about 300 mm(3), the mice were treated with letrozole. After initial response to letrozole, the tumors eventually became resistant (doubled their initial volume). The mice then were grouped to receive letrozole, exemestane (250 μg/d), entinostat (50 μg/d), or the combination of entinostat with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of entinostat with letrozole or exemestane were significantly slower than with the single agent (P < 0.05). Analysis of the letrozole-resistant tumors showed entinostat increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK, and p-Akt. However, the mechanism of action of entinostat in reversing acquired resistance did not involve epigenetic silencing but rather included posttranslational as well as transcriptional modulation of Her-2. Entinostat treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, entinostat also reduced Her-2 mRNA levels and its stability. Our results suggest that the HDAC inhibitor may reverse letrozole resistance in cells and tumors by modulating Her-2 expression and activity.
我们之前的研究表明，在固有耐药的肿瘤中，通过使用组蛋白去乙酰化酶（HDAC）抑制剂恩替诺特（entinostat）治疗，可以逆转雌激素受体（ER）的沉默。肿瘤随后对芳香化酶抑制剂（AI）来曲唑有反应。在这里，我们研究了在获得性来曲唑耐药的肿瘤中，恩替诺特是否可以恢复 ER。去卵巢的裸鼠接种 MCF-7Ca 细胞，并用雄烯二酮（Δ（4）A），芳香化的底物进行补充。当肿瘤达到约 300mm³时，给小鼠施用来曲唑。来曲唑初始反应后，肿瘤最终产生耐药性（体积增加一倍）。然后，将小鼠分为接受来曲唑、依西美坦（250μg/d）、恩替诺特（50μg/d）或恩替诺特与来曲唑或依西美坦联合治疗 26 周的组。与单独使用来曲唑或依西美坦相比，联合使用恩替诺特与来曲唑或依西美坦的肿瘤生长速度明显较慢（P<0.05）。对来曲唑耐药肿瘤的分析表明，恩替诺特增加了 ERα表达和芳香酶活性，但下调了 Her-2、p-Her-2、p-MAPK 和 p-Akt。然而，恩替诺特逆转获得性耐药的作用机制不是通过表观遗传沉默，而是包括 Her-2 的翻译后和转录调节。恩替诺特治疗降低了 Her-2 蛋白与 HSP-90 的结合，可能是通过降低 Her-2 蛋白的稳定性。此外，恩替诺特还降低了 Her-2mRNA 水平及其稳定性。我们的结果表明，HDAC 抑制剂可能通过调节 Her-2 的表达和活性来逆转来曲唑耐药。
