Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.
Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.
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DOI：
10.1101/gad.305631.117
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发表时间：
2017-11-15
影响因子：
10.5
通讯作者：
Schneider RJ
中科院分区：
文献类型：
--
作者：
Geter PA;Ernlund AW;Bakogianni S;Alard A;Arju R;Giashuddin S;Gadi A;Bromberg J;Schneider RJ
盖特等人。表明他莫昔芬耐药性涉及 Runx2 和其他 mRNA 选择性地将 mRNA 翻译重编程为抗雌激素状态。研究表明，他莫昔芬抗性翻译重编程是通过 eIF4E 表达增加以及 mTOR 过度活跃而增加其可用性来介导的，并且需要通过增加 MNK 活性来磷酸化 eIF4E Ser209。大多数乳腺癌表达雌激素受体 (ER+)，并采用抗雌激素疗法进行治疗，尤其是绝经前女性的他莫昔芬。然而，他莫昔芬耐药性是导致大部分乳腺癌死亡的原因。使用小分子抑制剂、磷酸模拟蛋白、他莫昔芬敏感和他莫昔芬耐药乳腺癌细胞、他莫昔芬耐药患者来源的异种移植模型、患者肿瘤组织以及全基因组转录和翻译研究，我们表明他莫昔芬耐药涉及Runx2和其他mRNA选择性mRNA翻译重编程至抗雌激素状态。研究表明，他莫昔芬抗性翻译重编程是通过 eIF4E 表达增加以及 mTOR 过度活跃而增加其可用性来介导的，并且需要通过增加 MNK 活性来磷酸化 eIF4E Ser209。只有通过降低 eIF4E 表达或 mTOR 活性并阻断 eIF4E 的 MNK1 磷酸化，才能恢复对他莫昔芬的再敏化。因他莫昔芬耐药而特异性翻译上调的 mRNA 包括 Runx2，它抑制 ER 信号传导和雌激素反应并促进乳腺癌转移。沉默 Runx2 可显着恢复他莫昔芬的敏感性。对他莫昔芬耐药但对他莫昔芬不敏感的 ER+ 乳腺癌患者标本也显示出 eIF4E 的 MNK 磷酸化强烈增加。因此，eIF4E 水平、可用性和磷酸化通过选择性 mRNA 翻译重编程促进 ER+ 乳腺癌中的他莫昔芬耐药性
Geter et al. show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming
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