Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance
Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance
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DOI：
10.4161/auto.5.3.7784
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发表时间：
2009-04-01
期刊：
影响因子：
13.3
通讯作者：
Barrett, John T.
中科院分区：
文献类型：
--
作者：
Schoenlein, Patricia V.;Periyasamy-Thandavan, Sudharsan;Barrett, John T.
抗雌激素，通过与ERα结合并阻断雌激素结合的ERα在乳腺癌细胞中的促生长作用而发挥其药理作用。他莫昔芬治疗主要诱导细胞停滞(生长停滞)，存活的乳腺癌细胞通常获得他莫昔芬耐药性。体外研究已经确定了许多获得性抗雌激素耐药的临床相关机制。我们最近的研究(摩尔癌症疗法2008；7：2977-87)现在证明自噬(也被称为宏自噬)对抗雌激素抵抗的发展至关重要。在自噬受到损害的条件下，包括药物抑制剂和针对beclin 1基因的RNAi治疗，抗雌激素4-羟基三苯氧胺(4-OHT)的细胞毒性(死亡诱导作用)显著增加。4-羟色胺是他莫昔芬的活性代谢物，常用于体外研究。以4-羟色胺为选择药物的分步选药方案，建立了抗雌激素耐药的乳腺癌细胞系。对一个具有代表性的耐药细胞系的分析表明，这些细胞维持高水平的抗雌激素诱导的自噬的能力增强了，而不会进展到死亡。重要的是，在4-羟色胺处理的抗雌激素抵抗细胞中，自噬功能的阻断诱导了强大的死亡反应。这些数据提供了强有力的证据表明，在抗雌激素攻击和进展到抗雌激素耐药期间，自噬是细胞存活的关键机制。我们讨论了阻断自噬功能以显著减少抗雌激素耐药乳腺癌细胞的潜在益处。
antiestrogen, exerts its pharmacological action by binding to ER alpha and blocking the growth-promoting action of estrogen-bound ER alpha in breast cancer cells. Tamoxifen treatment primarily induces cytostasis (growth arrest) and the surviving breast cancer cells commonly acquire tamoxifen resistance. Numerous clinically-relevant mechanisms of acquired antiestrogen resistance have been identified by in vitro studies. Our recent studies (Mol Cancer Ther 2008; 7:2977-87) now demonstrate that autophagy (also referred to as macroautophagy) is critical to the development of antiestrogen resistance. Under conditions of compromised autophagy, including treatments with pharmacological inhibitors and RNAi targeting of the beclin 1 gene, the cytotoxicity (death-inducing effects) of the antiestrogen 4-hydroxytamoxifen (4-OHT) was significantly increased. 4-OHT is an active metabolite of tamoxifen commonly used for in vitro studies. A step-wise drug selection protocol, using 4-OHT as the selecting drug, established antiestrogen-resistant breast cancer cell lines. Analysis of a representative resistant cell line showed an increased ability of the cells to sustain high levels of antiestrogen-induced autophagy without progression to death. Importantly, blockade of autophagosome function in the 4-OHT treated, antiestrogen-resistant cells induced a robust death response. These data provide strong evidence that autophagy is a key mechanism of cell survival during antiestrogen challenge and progression to antiestrogen resistance. We discuss the potential benefit of blocking autophagosome function to significantly reduce the emergence of antiestrogen-resistant breast cancer cells.