HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2.
HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2.
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DOI：
10.1158/1535-7163.mct-13-0345
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发表时间：
2013-12
影响因子：
5.7
通讯作者：
Brodie AH
中科院分区：
文献类型：
--
作者：
Sabnis GJ;Goloubeva OG;Kazi AA;Shah P;Brodie AH
我们之前的研究表明，在先天性耐药肿瘤中，雌激素受体（ER）的沉默可以通过组蛋白去乙酰化酶（HDAC）抑制剂恩替诺他（ENT）治疗逆转。肿瘤对芳香酶抑制剂（AIs）来曲唑有反应。在此，我们研究了耳鼻喉科是否可以恢复获得性来曲唑耐药肿瘤的ER。切除卵巢的胸腺小鼠接种MCF-7Ca细胞，补充雄烯二酮（Δ4A），芳香化底物。当肿瘤达到~300mm3时，给予来曲唑治疗。在对来曲唑有初步反应后，肿瘤最终产生耐药性（其初始体积增加一倍）。各组小鼠分别给予来曲唑、依西美坦（250μg/d）、耳鼻喉科（50μg/d）或来曲唑、依西美坦联合耳鼻喉科26周。来曲唑或依西美坦联合治疗小鼠肿瘤的生长速度明显慢于单用（p<0.05）。对来曲唑耐药肿瘤的分析显示，ENT增加了ERα表达和芳香化酶活性，但下调了Her-2、p-Her-2、p-MAPK和p-Akt。然而，ENT逆转获得性耐药的作用机制并不涉及表观遗传沉默，而是包括Her-2的翻译后和转录调节。耳鼻喉科治疗降低了Her-2蛋白与热休克蛋白-90的关联，可能是通过降低Her-2蛋白的稳定性。此外，ENT还降低了Her-2 mRNA水平及其稳定性。我们的研究结果表明，HDAC抑制剂可能通过调节Her-2的表达和活性来逆转细胞和肿瘤对来曲唑的耐药性。
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 (ENT). Tumors were then responsive to aromatase inhibitor (AIs) letrozole. Here, we investigated whether ER in the acquired letrozole resistant tumors could be restored with ENT. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ4A), the aromatizable substrate. When the tumors reached ~300mm3, 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 (250μg/day), ENT (50μg/day) or the combination of ENT with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of ENT with letrozole or exemestane were significantly slower than with the single agent (p<0.05). Analysis of the letrozole resistant tumors showed ENT increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK and p-Akt. However, the mechanism of action of ENT in reversing acquired resistance did not involve epigenetic silencing, but rather included post-translational as well as transcriptional modulation of Her-2. ENT treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, ENT 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.