The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis.
The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis.
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HER4/4ICD雌激素受体共激活剂和仅BH3蛋白是他莫昔芬诱导的凋亡的效应因子。
DOI：
10.1158/0008-5472.can-08-0538
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Jones, Frank E.
中科院分区：
文献类型：
--
作者：
Naresh, Anjali;Thor, Ann D.;Edgerton, Susan M.;Torkko, Kathleen C.;Kumar, Rakesh;Jones, Frank E.
超过40%的接受他莫昔芬治疗的乳腺癌患者表现出新发或获得性肿瘤耐药。最近的临床证据表明，HER 4表达的缺失是他莫昔芬耐药的独立标志物。在与临床观察的直接确证中，在他莫昔芬敏感的MCF-7和T47 D乳腺肿瘤细胞系中抑制HER 4表达导致对他莫昔芬诱导的细胞凋亡的抗性。此外，HER 4表达在获得性他莫昔芬耐药的三个独立MCF-7模型中丢失。HER 4胞内结构域（4 ICD）是一种独立的信号传导核蛋白，作为一种有效的ERα共激活剂发挥作用。此外，线粒体4 ICD作为促凋亡的BH 3蛋白发挥作用。他莫昔芬破坏雌激素驱动的ERα和4 ICD之间的相互作用，同时促进4 ICD BH 3-only蛋白的线粒体积累。BCL-2抑制他莫昔芬诱导的细胞凋亡和他莫昔芬独立于BAX激活巴克进一步支持了4 ICD在他莫昔芬诱导的细胞凋亡过程中的作用。最后，在异种移植模型中，重新引入HER 4，而不是具有突变的BH 3结构域的HER 4，恢复了他莫昔芬对他莫昔芬抗性TamR细胞的敏感性。临床上，肿瘤表达核4 ICD的乳腺癌患者对他莫昔芬治疗有反应，随访14年后没有临床失败的报道，而20%缺乏核4 ICD表达的患者在诊断后10年内死于疾病。我们鉴定HER 4/4 ICD BH 3-only蛋白作为他莫昔芬作用的关键介质，为4 ICD在人类癌症中提供了临床重要作用，并揭示了预测患者对他莫昔芬治疗反应的潜在肿瘤标志物。
Greater than 40% of breast cancer patients treated with tamoxifen exhibit de novo or acquired tumor resistance. Recent clinical evidence indicates that loss of expression of HER4 is an independent marker for tamoxifen resistance. In direct corroboration with clinical observations, suppression of HER4 expression in the tamoxifen sensitive MCF-7 and T47D breast tumor cell lines resulted in resistance to tamoxifen induced apoptosis. Furthermore, HER4 expression was lost in three independent MCF-7 models of acquired tamoxifen resistance. The HER4 intracellular domain (4ICD) is an independently signaling nuclear protein which functions as a potent ERα coactivator. In addition, mitochondrial 4ICD functions as a proapoptotic BH3-only protein. Tamoxifen disrupts an estrogen driven interaction between ERα and 4ICD while promoting mitochondrial accumulation of the 4ICD BH3-only protein. BCL-2 inhibition of tamoxifen induced apoptosis and tamoxifen activation of BAK independent of BAX further supports a role for 4ICD during tamoxifen induced apoptosis. Finally, reintroduction of HER4, but not HER4 with a mutated BH3 domain, restores tamoxifen sensitivity to tamoxifen resistant TamR cells in a xenograph model. Clinically, breast cancer patients with tumor expression of nuclear 4ICD responded to tamoxifen therapy with no clinical failures reported after 14 years of follow-up, whereas 20% patients lacking nuclear 4ICD expression succumbed to their disease within 10 years of diagnosis. Our identification of the HER4/4ICD BH3-only protein as a critical mediator of tamoxifen action provides a clinically important role for 4ICD in human cancer and reveals a potential tumor marker to predict patient response to tamoxifen therapy.