文章：

一种用于识别对曲妥珠单抗治疗耐药患者的潜在生物标志物

A potential biomarker to identify patients resistant to trastuzumab treatment 

原文发布日期：2024-08-10 

英文摘要：

HER2-positive (HER2+) breast cancer accounts for 20–30% of all breast cancers. Although trastuzumab has significantly improved the survival of patients with HER2+ breast cancer, more than 70% of patients develop drug resistance within one year of treatment. Differential-gene-expression analysis of trastuzumab-sensitive and resistant HER2+ breast cancer cell lines from GSE15043 was performed to identify the biomarkers associated with trastuzumab resistance. Differential biomarker expression was confirmed in FFPE tissues collected from clinical HER2+ breast cancer tumor samples that were sensitive or resistant to trastuzumab treatment. UGT1A7, a member of the uronic acid transferase family, was associated with trastuzumab resistance. UGT1A7 expression was downregulated in trastuzumab-resistant tumor tissues and in a cell line that developed trastuzumab resistance (BT474TR). Overexpressing UGT1A7 in BT474TR restored their sensitivity to trastuzumab treatment, whereas downregulating UGT1A7 expression in parental cells led to trastuzumab resistance. Importantly, UGT1A7 localized to the endoplasmic reticulum and altered stress responses. Furthermore, downregulating UGT1A7 expression promoted epithelial-to-mesenchymal transition (EMT) by affecting TWIST, SNAIL, and GRP78 expression and the AMP-activated protein kinase signaling pathway, thus contributing to trastuzumab resistance. This study demonstrated the important role and novel mechanisms of UGT1A7 in tumor responses to trastuzumab. Low UGT1A7 expression plays an important role in EMT and contributes to trastuzumab resistance. UGT1A7 has the potential to be developed as a biomarker for identifying patients who are resistant to trastuzumab treatment. 

摘要翻译：

HER2阳性（HER2+）乳腺癌占所有乳腺癌的20%-30%。尽管曲妥珠单抗显著改善了HER2+乳腺癌患者的生存率，但超过70%的患者在治疗一年内会产生耐药性。本研究通过对GSE15043数据库中曲妥珠单抗敏感及耐药HER2+乳腺癌细胞系进行差异基因表达分析，旨在鉴定与曲妥珠单抗耐药相关的生物标志物。研究人员在临床收集的曲妥珠单抗敏感与耐药HER2+乳腺癌FFPE组织样本中验证了差异生物标志物的表达情况。研究发现尿苷二磷酸葡萄糖醛酸转移酶家族成员UGT1A7与曲妥珠单抗耐药相关：在耐药肿瘤组织及诱导建立的曲妥珠单抗耐药细胞系（BT474TR）中，UGT1A7表达显著下调。在BT474TR细胞中过表达UGT1A7可恢复其对曲妥珠单抗的敏感性，而在亲代细胞中下调UGT1A7表达则导致耐药性产生。重要的是，UGT1A7定位于内质网并调节应激反应。此外，下调UGT1A7表达通过影响TWIST、SNAIL和GRP78表达及AMP活化蛋白激酶信号通路，促进上皮间质转化（EMT）进程，从而介导曲妥珠单抗耐药。本研究揭示了UGT1A7在肿瘤对曲妥珠单抗应答中的重要功能和新机制：低表达的UGT1A7在EMT中起关键作用并导致曲妥珠单抗耐药，未来有望开发作为识别曲妥珠单抗耐药患者的生物标志物。

原文链接：

A potential biomarker to identify patients resistant to trastuzumab treatment