A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients
A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients
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DOI：
10.1093/hmg/ddr390
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Pages, Gilles
中科院分区：
文献类型：
--
作者：
Griseri, Paola;Bourcier, Christine;Pages, Gilles
转录后调控在细胞分化和增殖中起着核心作用。在参与该机制的调节因子中，Tristetraprolin（ZFP 36或TTP）是RNA结合蛋白家族的原型，其结合mRNA的3 'UTR中富含腺苷酸和尿苷酸（Au）的序列，这促进其生理衰变。在这里，我们研究了TTP是否与乳腺癌的肿瘤侵袭性相关，并且是这种肿瘤的一个新的预后因素。通过免疫印迹分析，我们确定了TTP蛋白在不同的乳腺癌细胞系中的量，并发现侵袭性和转移潜力之间呈负相关。TTP mRNA水平在细胞系中变化很大，与蛋白水平无关。有趣的是，通过对不表达TTP蛋白的Hs 578 T细胞中的整个TTP编码区进行测序，我们确定了一个同义多态性（rs3746083），该多态性与HER 2阳性乳腺癌患者对赫赛汀/曲妥珠单抗缺乏应答具有统计学显著相关性。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，并显示了相对于野生型，与变体等位基因相关的蛋白质翻译的影响。这些数据强调了同义变异对基因表达的重要性，以及TTP基因多态性作为乳腺癌预后标志物的潜在作用。
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.