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首页> 外文期刊>British Journal of Cancer >ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels
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ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels

机译： ATM 在散发性乳腺癌的双链断裂修复途径失调中起主要作用，并且在mRNA和蛋白质水平上都是独立的预后标志物

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Background: Ataxia telangiectasia mutated (ATM) is a kinase that has a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks (DSB). In breast cancer, a low level of ATM was correlated with poor outcome; however, the molecular mechanism of this downregulation is still unclear. Methods: We used qRT–PCR assay to quantify mRNA levels of ATM gene in 454 breast tumours from patients with known clinical/pathological status and outcome; reverse phase protein arrays (RPPA) were used to assess the levels of ATM and 14 proteins in 233 breast tumours. Results: ATM mRNA was associated with poor metastasis-free survival (MFS) ( P =0.00012) on univariate analysis. ATM mRNA and protein levels were positively correlated ( P =0.00040). A low level of ATM protein was correlated with poorer MFS ( P =0.000025). ATM expression at mRNA or protein levels are independent prognostic factors on multivariate analysis ( P =0.00046 and P =0.00037, respectively). The ATM protein level was positively correlated with the levels of six proteins of the DSB repair pathway: H2AX ( P <0.0000001), XRCC5 ( P <0.0000001), NBN ( P <0.0000001), Mre11 ( P =0.0000029), Rad50 ( P =0.0064), and TP53BP1 ( P =0.026), but not with proteins involved in other pathways that are altered in cancer. Low expression of ATM protein was significantly associated with high miR-203 expression ( P =0.011). Conclusion: We confirmed that ATM expression is an independent prognostic marker at both RNA and protein levels. We showed that alteration of ATM is involved in dysregulation of the DSB repair pathway. Finally, miR-203 may be responsible for downregulation of ATM in breast cancers.
机译：背景：共济失调毛细血管扩张症（ATM）是一种激酶，通过激活细胞周期检查点并促进DNA双链断裂（DSB）的修复，在维持基因组完整性中起着核心作用。在乳腺癌中，低水平的ATM与不良预后相关。然而，这种下调的分子机制仍不清楚。方法：我们使用qRT-PCR分析定量了454例临床/病理状况和结果已知的乳腺肿瘤中ATM基因的mRNA水平。反相蛋白质阵列（RPPA）用于评估233个乳腺肿瘤中ATM和14种蛋白质的水平。结果：单因素分析显示，ATM mRNA与无转移生存期差（MFS）相关（P = 0.00012）。 ATM mRNA和蛋白质水平呈正相关（P = 0.00040）。低水平的ATM蛋白与较差的MFS相关（P = 0.000025）。在多变量分析中，mRNA或蛋白水平的ATM表达是独立的预后因素（分别为P = 0.00046和P = 0.00037）。 ATM蛋白水平与DSB修复途径的六种蛋白水平呈正相关：H2AX（P <0.0000001），XRCC5（P <0.0000001），NBN（P <0.0000001），Mre11（P = 0.0000029），Rad50（P = 0.0064）和TP53BP1（P = 0.026），但不包含参与癌症中其他途径改变的蛋白质。 ATM蛋白的低表达与miR-203的高表达显着相关（P = 0.011）。结论：我们证实ATM表达在RNA和蛋白质水平上都是独立的预后标志物。我们表明，ATM的改变与DSB修复途径的失调有关。最后，miR-203可能导致乳腺癌中ATM的下调。

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