University Nice-Sophia Antipolis Institute of Developmental Biology and Cancer, CNRS UMR 6543, France.
Hum Mol Genet. 2011 Dec 1;20(23):4556-68. doi: 10.1093/hmg/ddr390. Epub 2011 Aug 29.
Post-transcriptional regulation plays a central role in cell differentiation and proliferation. Among the regulatory factors involved in this mechanism, Tristetraprolin (ZFP36 or TTP) is the prototype of a family of RNA-binding proteins that bind to adenylate and uridylate (AU)-rich sequences in the 3'UTR of mRNAs, which promotes their physiological decay. Here, we investigated whether TTP correlates with tumor aggressiveness in breast cancer and is a novel prognostic factor for this neoplasia. By immunoblot analysis, we determined the amount of TTP protein in different breast cancer cell lines and found an inverse correlation between aggressiveness and metastatic potential. TTP mRNA levels were very variable among cells lines and did not correlate with protein levels. Interestingly, by sequencing the entire TTP coding region in Hs578T cells that do not express the TTP protein, we identified a synonymous polymorphism (rs3746083) that showed a statistically significant association with a lack of response to Herceptin/Trastuzumab in HER2-positive-breast cancer patients. Even though this genetic change did not modify the corresponding amino acid, we performed functional studies and showed an effect on protein translation associated with the variant allele with respect to the wild-type. These data underline the importance of synonymous variants on gene expression and the potential role of TTP genetic polymorphisms as a prognostic marker for breast cancer.
转录后调控在细胞分化和增殖中起着核心作用。在涉及该机制的调节因子中，Tristetraprolin（ZFP36 或 TTP）是 RNA 结合蛋白家族的原型，该家族蛋白结合 mRNA 3'UTR 中的腺苷酸和尿苷酸（AU）丰富序列，促进其生理降解。在这里，我们研究了 TTP 是否与乳腺癌的侵袭性相关，以及是否是该肿瘤的新的预后因素。通过免疫印迹分析，我们测定了不同乳腺癌细胞系中 TTP 蛋白的含量，发现侵袭性和转移潜能之间呈负相关。细胞系中 TTP mRNA 水平差异很大，与蛋白水平不相关。有趣的是，通过对不表达 TTP 蛋白的 Hs578T 细胞进行 TTP 编码区全序列测序，我们发现了一个同义多态性（rs3746083），与 HER2 阳性乳腺癌患者对曲妥珠单抗/赫赛汀无反应有统计学显著关联。尽管这种遗传变化没有改变相应的氨基酸，但我们进行了功能研究，显示与野生型相比，该变异等位基因与蛋白翻译相关。这些数据强调了同义变体对基因表达的重要性以及 TTP 遗传多态性作为乳腺癌预后标志物的潜在作用。
