Triple-negative breast cancer (TNBC) has poor clinical prognosis. Lack of TNBC-specific biomarkers prevents active clinical intervention. We reasoned that TNBC must have its specific signature due to the lack of three key receptors to distinguish TNBC from other types of breast cancer. We also reasoned that coupling methylation and gene expression as a single unit may increase the specificity for the detected TNBC signatures. We further reasoned that choosing the proper controls may be critical to increasing the sensitivity to identify TNBC-specific signatures. Furthermore, we also considered that specific drugs could target the detected TNBC-specific signatures. We developed a system to identify potential TNBC signatures. It consisted of (1) coupling methylation and expression changes in TNBC to identify the methylation-regulated signature genes for TNBC; (2) using TPBC (triple-positive breast cancer) as the control to detect TNBC-specific signature genes; (3) searching in the drug database to identify those targeting TNBC signature genes. Using this system, we identified 114 genes with both altered methylation and expression, and 356 existing drugs targeting 10 of the 114 genes. Through docking and molecular dynamics simulation, we determined the structural basis between sapropterin, a drug used in the treatment of tetrahydrobiopterin deficiency, and PTGS2, a TNBC signature gene involved in the conversion of arachidonic acid to prostaglandins. Our study reveals the existence of rich TNBC-specific signatures, and many can be drug target and biomarker candidates for clinical applications.

译文

三阴性乳腺癌 (TNBC) 临床预后较差。TNBC特异性生物标志物的缺乏阻碍了积极的临床干预。我们认为,由于缺乏三种关键受体来区分TNBC与其他类型的乳腺癌,TNBC必须具有其特定的特征。我们还认为,将甲基化和基因表达作为单个单元偶联可能会增加检测到的TNBC签名的特异性。我们进一步认为,选择适当的控件对于提高识别TNBC特定签名的敏感性可能至关重要。此外,我们还认为特定药物可以针对检测到的TNBC特异性特征。我们开发了一个识别潜在TNBC签名的系统。它由 (1) 结合甲基化和TNBC中的表达变化来鉴定TNBC的甲基化调节签名基因; (2) 以TPBC (三阳性乳腺癌) 为对照来检测TNBC特异性签名基因; (3) 在药物数据库中搜索以识别那些靶向TNBC签名基因。使用该系统,我们鉴定了114个具有改变的甲基化和表达的基因,并356了靶向10个114基因的现有药物。通过对接和分子动力学模拟,我们确定了用于治疗四氢生物蝶呤缺乏症的药物沙丙蝶呤与参与花生四烯酸向前列腺素转化的TNBC签名基因PTGS2之间的结构基础。我们的研究揭示了存在丰富的TNBC特异性签名,并且许多可能是临床应用的药物靶标和生物标志物候选者。

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