HER2 阳性 (HER2) 乳腺癌占所有乳腺癌的 20-30%。尽管曲妥珠单抗显着提高了HER2乳腺癌患者的生存率，但超过70%的患者在治疗一年内出现耐药性。对来自 GSE15043 的曲妥珠单抗敏感和耐药 HER2 乳腺癌细胞系进行差异基因表达分析，以确定与曲妥珠单抗耐药性相关的生物标志物。从对曲妥珠单抗治疗敏感或耐药的临床 HER2 乳腺癌肿瘤样本中收集的 FFPE 组织中证实了差异生物标志物表达。 UGT1A7 是糖醛酸转移酶家族的成员，与曲妥珠单抗耐药相关。 UGT1A7 表达在曲妥珠单抗耐药的肿瘤组织和产生曲妥珠单抗耐药的细胞系 (BT474TR) 中下调。 BT474TR 中 UGT1A7 的过度表达恢复了它们对曲妥珠单抗治疗的敏感性，而亲本细胞中 UGT1A7 表达的下调导致了曲妥珠单抗耐药。重要的是，UGT1A7 定位于内质网并改变应激反应。此外，下调 UGT1A7 表达通过影响 TWIST、SNAIL 和 GRP78 表达以及 AMP 激活蛋白激酶信号通路促进上皮间质转化 (EMT)，从而导致曲妥珠单抗耐药。这项研究证明了 UGT1A7 在肿瘤对曲妥珠单抗反应中的重要作用和新机制。 UGT1A7 低表达在 EMT 中发挥重要作用，并导致曲妥珠单抗耐药。 UGT1A7 有潜力被开发为生物标志物，用于识别对曲妥珠单抗治疗耐药的患者。© 2024。作者，获得 Springer Nature America, Inc. 的独家许可。

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.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.