Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time
Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time
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DOI：
10.1073/pnas.1115188108
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发表时间：
2011-11-22
影响因子：
11.1
通讯作者：
Jordan, V. Craig
中科院分区：
文献类型：
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作者：
Ariazi, Eric A.;Cunliffe, Heather E.;Jordan, V. Craig
在实验室研究中，乳腺癌对长期激素治疗的获得性耐药在5年内经历了两个阶段。I期在1年内发展，并且肿瘤生长在17 β-雌二醇（E-2）或他莫昔芬的作用下发生。治疗5年后出现II期耐药，他莫昔芬仍然刺激生长;然而，E-2却自相矛盾地诱导细胞凋亡。这一发现是临床使用雌激素治疗晚期抗乳腺癌耐药乳腺癌的基础。我们通过分析MCF-7细胞变体中随时间（2-96 h）的基因表达来探究E-2诱导的细胞凋亡，所述MCF-7细胞变体是雌激素依赖性的（WS 8）或对雌激素剥夺具有抗性，并且对E-2诱导的细胞凋亡不敏感（2A）或敏感（5C）。我们开发了一种方法，称为微分曲线下面积分析，确定了基因独特的调控E-2在5C细胞相比，WS 8和2A细胞，因此，与E-2诱导的细胞凋亡。雌激素信号，内质网应激（ERS）和炎症反应基因之间的5C特异性基因的过度。已鉴定的ERS基因表明E-2抑制蛋白质折叠、翻译和脂肪酸合成。同时，诱导ERS相关凋亡基因Bcl-2相互作用的细胞死亡介质（BIM; BCL 2L 11）和caspase-4（CASP 4）等。半胱天冬酶肽抑制剂组的评估显示CASP 4抑制剂z-LEVD-favorite在阻断E-2诱导的细胞凋亡方面最活跃。此外，z-LEVD-fetamine完全阻止聚（ADP-核糖）聚合酶（PARP）裂解，E-2抑制的生长和凋亡形态。上调的促炎基因包括IL、IFN和花生四烯酸相关基因。功能测试表明，花生四烯酸和E-2相互作用，超加性诱导细胞凋亡。因此，这些数据表明，E-2诱导凋亡，通过ERS和炎症反应，在先进的抗肿瘤药耐药乳腺癌。
In laboratory studies, acquired resistance to long-termantihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17 beta-estradiol (E-2) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E-2 paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E-2-induced apoptosis by analysis of gene expression across time (2-96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E-2-induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E-2 in 5C cells compared with both WS8 and 2A cells and hence, were associated with E-2-induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E-2 inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E-2-induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E-2-inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E-2 interacted to superadditively induce apoptosis. Therefore, these data indicate that E-2 induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.