Department of Biological Sciences and Cancer Research Center, University of South Carolina, Columbia, SC, USA.
Int J Cancer. 2013 Feb 1;132(3):E128-38. doi: 10.1002/ijc.27789. Epub 2012 Sep 18.
The RNA-binding proteins TTP and HuR control expression of numerous genes associated with breast cancer pathogenesis by regulating mRNA stability. However, the role of genetic variation in TTP (ZFP36) and HuR (ELAVL1) genes is unknown in breast cancer prognosis. A total of 251 breast cancer patients (170 Caucasians and 81 African-Americans) were enrolled and followed up from 2001 to 2011 (or until death). Genotyping was performed for 10 SNPs in ZFP36 and 7 in ELAVL1 genes. On comparing both races with one another, significant differences were found for clinical and genetic variables. The influence of genetic polymorphisms on survival was analyzed by using Cox-regression, Kaplan-Meier analysis and the log-rank test. Univariate (Kaplan-Meier/Cox-regression) and multivariate (Cox-regression) analysis showed that the TTP gene polymorphism ZFP362 A > G was significantly associated with poor prognosis of Caucasian patients (HR = 2.03; 95% CI = 1.09-3.76; p = 0.025; log-rank p = 0.022). None of the haplotypes, but presence of more than six risk genotypes in Caucasian patients, was significantly associated with poor prognosis (HR=2.42; 95% CI = 1.17-4.99; p = 0.017; log-rank p = 0.007). The effect of ZFP362 A > G on gene expression was evaluated from patients' tissue samples. Both TTP mRNA and protein expression was significantly decreased in ZFP362 G allele carriers compared to A allele homozygotes. Conversely, upregulation of the TTP-target gene COX-2 was observed ZFP362 G allele carriers. Through its ability to attenuate TTP gene expression, the ZFP36*2 A > G gene polymorphism has appeared as a novel prognostic breast cancer marker in Caucasian patients.
TTP 和 HuR 这两种 RNA 结合蛋白通过调节 mRNA 稳定性来控制许多与乳腺癌发病机制相关的基因的表达。然而，TTP（ZFP36）和 HuR（ELAVL1）基因中的遗传变异在乳腺癌预后中的作用尚不清楚。总共招募了 251 名乳腺癌患者（170 名白人和 81 名非裔美国人），并从 2001 年到 2011 年（或直至死亡）进行随访。对 ZFP36 中的 10 个 SNP 和 ELAVL1 中的 7 个 SNP 进行了基因分型。在比较两个种族时，发现临床和遗传变量存在显著差异。使用 Cox 回归、Kaplan-Meier 分析和对数秩检验分析遗传多态性对生存的影响。单变量（Kaplan-Meier/Cox 回归）和多变量（Cox 回归）分析显示，TTP 基因多态性 ZFP362 A > G 与白人患者的不良预后显著相关（HR=2.03；95%CI=1.09-3.76；p=0.025；对数秩检验 p=0.022）。虽然不存在单倍型，但白人患者中存在超过六个风险基因型与不良预后显著相关（HR=2.42；95%CI=1.17-4.99；p=0.017；对数秩检验 p=0.007）。从患者的组织样本中评估了 ZFP362 A > G 对基因表达的影响。与 A 等位基因纯合子相比，ZFP362 G 等位基因携带者的 TTP mRNA 和蛋白表达均显著降低。相反，观察到 TTP 靶基因 COX-2 的上调。通过衰减 TTP 基因表达的能力，ZFP362 A > G 基因多态性似乎成为白人患者的一种新的乳腺癌预后标志物。
