EPRS is a critical regulator of cell proliferation and estrogen signaling in ER+ breast cancer.
EPRS is a critical regulator of cell proliferation and estrogen signaling in ER+ breast cancer.
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DOI：
10.18632/oncotarget.11870
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Irie HY
中科院分区：
文献类型：
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作者：
Katsyv I;Wang M;Song WM;Zhou X;Zhao Y;Park S;Zhu J;Zhang B;Irie HY
氨酰tRNA合成酶（ARSs）是一类在细胞翻译中具有高度保守的管家功能的酶。最近的证据表明，ARS基因可能参与了广泛的细胞过程，并可能有助于自身免疫性疾病，癌症和其他疾病的病理学。几项研究表明谷氨酰脯氨酰tRNA合成酶（EPRS）在乳腺癌中的作用，尽管没有人确定EPRS如何促进致癌的任何潜在机制。在这项研究中，我们确定了EPRS在TCGA和METABRIC队列中的雌激素受体阳性（ER+）人类乳腺肿瘤中上调，在两个数据集中近50%的样本中拷贝数增加。在TCGA和METABRIC数据集中，EPRS表达与ER+肿瘤患者的总生存期降低相关。EPRS表达也与接受他莫昔芬单药辅助治疗5年的患者远端无复发生存率降低相关，并且EPRS相关基因高度富集预测他莫昔芬不良反应的基因。我们证明了EPRS对他莫昔芬耐药ER+乳腺癌细胞增殖的必要性，而不是ER-乳腺癌细胞。转录组学分析显示EPRS调控细胞周期和雌激素反应基因。最后，我们构建了一个基于2500多个ER+乳腺肿瘤样本的致病基因网络，以建立一个EPR-雌激素信号通路。EPRS及其受调节的雌激素基因网络可能为靶向目前抗雌激素难治的ER+乳腺癌提供一种有希望的替代方法。
Aminoacyl tRNA synthetases (ARSs) are a class of enzymes with well-conserved housekeeping functions in cellular translation. Recent evidence suggests that ARS genes may participate in a wide array of cellular processes, and may contribute to the pathology of autoimmune disease, cancer, and other diseases. Several studies have suggested a role for the glutamyl prolyl tRNA synthetase (EPRS) in breast cancers, although none has identified any underlying mechanism about how EPRS contributes to carcinogenesis. In this study, we identified EPRS as upregulated in estrogen receptor positive (ER+) human breast tumors in the TCGA and METABRIC cohorts, with copy number gains in nearly 50% of samples in both datasets. EPRS expression is associated with reduced overall survival in patients with ER+ tumors in TCGA and METABRIC datasets. EPRS expression was also associated with reduced distant relapse-free survival in patients treated with adjuvant tamoxifen monotherapy for five years, and EPRS-correlated genes were highly enriched for genes predictive of a poor response to tamoxifen. We demonstrated the necessity of EPRS for proliferation of tamoxifen-resistant ER+ breast cancer, but not ER- breast cancer cells. Transcriptomic profiling showed that EPRS regulated cell cycle and estrogen response genes. Finally, we constructed a causal gene network based on over 2500 ER+ breast tumor samples to build up an EPRS-estrogen signaling pathway. EPRS and its regulated estrogenic gene network may offer a promising alternative approach to target ER+ breast cancers that are refractory to current anti-estrogens.