Up-regulation of TLK1B by eIF4E overexpression predicts cancer recurrence in irradiated patients with breast cancer
Up-regulation of TLK1B by eIF4E overexpression predicts cancer recurrence in irradiated patients with breast cancer
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DOI：
10.1016/j.surg.2006.05.001
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发表时间：
2006-08-01
期刊：
影响因子：
3.8
通讯作者：
Li, Benjamin D.
中科院分区：
文献类型：
--
作者：
Wolfort, Ryan;de Benedetti, Arrigo;Li, Benjamin D.
背景资料。真核细胞起始因子4E(EIF4E)是RNA解旋酶复合体的重要组成部分，在长和/或复杂的5‘非翻译区信使RNA的翻译中起重要作用，它的过表达似乎影响乳腺癌患者的恶性转化和预测癌症复发，与淋巴结状态无关。Tousle样激酶(TLK1B)是一种哺乳动物苏氨酸激酶，在信使RNA中有一个长5‘非翻译区。在体外，eIF4E过表达的恶性细胞似乎有相应的TLK1B升高。此外，TLK1B使组蛋白3磷酸化，组蛋白3是一种参与染色质组装的蛋白质，在细胞系的辐射抗性中发挥着不可或缺的作用。我们的假设是，eIF4E高表达的乳腺癌患者TLK1B增加，辅助放射治疗后复发的风险更高。一项前瞻性研究收集了158名I-III期乳腺癌患者，该研究旨在检测接受辅助放射治疗的患者的癌症复发情况。标准化的监测和治疗方案被用来最大限度地提高治疗的一致性，并检测研究的主要终点--癌症复发。所有患者都接受了辅助放射治疗，要么是针对高危结节阳性疾病，要么是作为保乳治疗的一部分。免疫印迹法检测TLK1B和eIF4E水平。统计分析包括Spearman相关分析、Kaplan-Meier方法生存分析、对数等级检验和Cox比例风险模型。在所有乳腺癌组织中，eIF4E(15.4+/-0.6，平均值+/-SD)和TLX1B(18.8+/-1.5)均升高。EIF4E过表达增加与TLK1B增加高度相关(r=0.35；P<；0.0001，Spearman系数)。根据eIF4E和TLK1B增加的程度，患者的三分分布表明eIF4E最高和TLK1B最高的患者的癌症复发率较高(分别为P=0.015和0.049，LOG RANK检验)。在调整了疾病分期、年龄和雌孕激素受体状态后，数据显示高TLK1B组患者辅助放射治疗后癌症复发的相对风险是低TLK1B组的3.0倍(P=0.036；95%CI，1.0-5.0)。在I-III期乳腺癌标本中，eIF4E的过度表达与TLK1B的升高有关。肿瘤标本中TLK1B的高水平升高与辅助放射治疗后肿瘤复发的风险较高有关。对放射治疗的抵抗可能是乳腺癌eIF4E过度表达预示预后较差的机制。
Background. The overexpression of eukaryotic initiation factor 4E (eIF4E), which is a critical component of the RNA helicase complex important in the translation of messenger RNAs with long and/or complex 5' untranslated regions, appears to impact malignant transformation and predict cancer recurrence in patients with breast cancer, independent of nodal status. Tousled-like kinase (TLK1B) is a mammalian threonine kinase with a long 5' untranslated regions in the messenger RNA. In vitro, malignant cells with eIF4E overexpression appear to have corresponding TLK1B elevation. Additionally TLK1B phosphorylates histone 3, which is a protein that is involved in chromatin assembly, plays an integral role, in radioresistance in cell lines. Our hypothesis is that patients with breast cancer with high eIF4E overexpression have increased TLK1B and a higher risk for recurrence after adjuvant radiation therapy.Methods. One hundred fifty-eight patients with stage I to III breast cancer were accrued in a prospective study that was designed to detect cancer recurrence in patients who had been treated with adjuvant radiation therapy. A standardized surveillance and treatment protocol was used to maximize treatment homogeneity and to detect the study primary end point, cancer recurrence. All patients received adjuvant radiation therapy either for high-risk node-positive disease or as a part of breast conservation therapy. TLK1B and eIF4E levels were quantified by Western blot. Statistical analysis was performed and included Spearman correlation, survival analysis by the Kaplan-Meier method, log-rank test, and Cox proportional hazard model.Results. Both eIF4E (15.4 +/- 0.6, mean +/- SD) and TLX1B (18.8 +/- 1.5) were increased in all breast cancer specimens. Increasing eIf4E overexpression was correlated highly with increasing TLK1B (r = 0.35; P < .0001, Spearman coefficient). Tertile distribution of patients, based on the degree of eIF4E and TLK1B increase, demonstrated that the patients in the highest eIF4E group and the highest TLK1B group had a higher rate of cancer recurrences (P = .015 and .049, log rank test, respectively). After adjustment for stage of disease, age, and estrogen/progesterone receptor status, data showed that patients in the highest TLK1B group had a 3.0-fold increase in relative risk for cancer recurrence after adjuvant radiation therapy (P = .036; 95 % CI, 1.0-5.0), compared with patients in the low TLK1B group.Conclusion. The overexpression of eIF4E is correlated with TLK1B increase in cancer specimens from patients with stage I to III breast cancer. High TLK1B increase in tumor specimens was associated with a higher risk for cancer recurrence after adjuvant radiation therapy. Resistance to radiotherapy may be I mechanism whereby eIF4E overexpression in breast cancer portends a worse prognosis.