本研究旨在寻找对乳腺癌具有影响的潜在HER2突变，并研究其潜在机制。首先，本研究在靶向下一代测序（tNGS）平台上调查了238对乳腺癌和癌旁组织样本。使用CCK-8细胞增殖试验和克隆形成试验，研究了突变是否对乳腺癌细胞产生增殖作用。此外，对L796P突变型和野生型MCF-7细胞系进行了基于质谱的比较蛋白质组和磷酸化组学分析。在识别的突变中，发现了一种新的HER2 L796P突变，它促进了乳腺癌细胞的增殖并对拉帕替尼具有耐药性，这通过CCK-8细胞增殖试验和克隆形成试验得到证实。生物信息学分析显示，在L796P突变细胞中，RAS家族蛋白和ERK磷酸化蛋白显著增加。基因本体（GO）分析揭示了L796P突变影响MAPK和PI3K-AKT-TOR通路上游基因的乳腺癌功能。本研究证明了一种罕见的HER2 L796P突变可能成为乳腺癌临床治疗的潜在靶点。© 2023 Wiley-VCH GmbH.

This research aimed to find potential HER2 mutations that would have an impact on breast cancer and investigate the underlying mechanism.This study first investigated 238 pairs of breast cancer and para-cancerous tissue samples from patients on the targeted next-generation sequencing (tNGS) platform. CCK-8 and clone formation assay were used to investigate whether the mutation exerts proliferative effects on breast cancer cells. In addition, mass spectrometry-based comparative proteomic and phosphoproteomic analyses of the mutation types and wild types of MCF-7 cell lines were carried out.Among the identified mutations, a new mutation HER2 L796P promoted the proliferation of breast cancer cells and had resistance to lapatinib using CCK-8 cell proliferation assay and clone formation assay. The bioinformatic analysis showed that RAS family proteins and ERK phosphorylated proteins significantly increased in the L796P mutant cells. The Gene Ontology (GO) analysis revealed that L796P mutation affected the function of breast cancer at the level of upstream genes in the MAPK and PI3K-AKT-TOR pathways.This study demonstrated that a rare mutation HER2 L796P could be a potential therapeutic target for the clinical management of breast cancer.© 2023 Wiley-VCH GmbH.