Samaddar Julia S, Gaddy Virgil T, Duplantier Jennifer, Thandavan Sudharsan Periyasamy, Shah Manish, Smith Marlena J, Browning Darren, Rawson Jim, Smith Sylvia B, Barrett John T, Schoenlein Patricia V
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.
Mol Cancer Ther. 2008 Sep;7(9):2977-87. doi: 10.1158/1535-7163.MCT-08-0447.
This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor-positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT-induced cell death, but not 4-OHT-induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT-resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer.
本研究确定巨自噬是雌激素受体阳性（ER+）乳腺癌细胞在用4-羟基他莫昔芬（4-OHT）治疗过程中细胞存活的关键机制。这种选择性雌激素受体调节剂是他莫昔芬的活性代谢产物，常用于治疗乳腺癌。我们的研究有以下主要发现：（a）体外经4-OHT处理的乳腺癌细胞中只有20%至25%通过半胱天冬酶依赖性细胞死亡而死亡；更常见的是，经抗雌激素处理的ER+乳腺癌细胞巨自噬水平升高且具有活力；（b）泛半胱天冬酶抑制剂z-VAD-fmk可阻断4-OHT诱导的细胞死亡，但不能阻断4-OHT诱导的巨自噬，这有力证明抗雌激素治疗的这两种结果并非必然相关；（c）从ER+乳腺癌细胞中筛选出的4-OHT耐药细胞在不诱导半胱天冬酶依赖性细胞死亡的情况下，抗雌激素诱导的巨自噬能力增强；（d）4-OHT与自噬体功能抑制剂联合使用时，可诱导ER+、4-OHT耐药乳腺癌细胞发生强烈的、半胱天冬酶依赖性凋亡。据我们所知，这些研究首次证明巨自噬在抗雌激素耐药的发生中起关键作用。我们认为靶向自噬体功能将提高ER+乳腺癌激素治疗的疗效。
