Background Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis. Methods Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein–protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay. Results We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes—ACLY, HSPD1, PFAS, GART, TXN, HSPH1, HSPE1, IRAS, TRAP1, and ATIC—might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes (TXN, HSPD1, HSPH1 and ATIC) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance (P = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance. Conclusion This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.

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乳腺癌中与他莫昔芬耐药相关的关键基因的鉴定和表征

背景 乳腺癌对他莫昔芬的耐药性是临床实践中未解决的问题。本研究的目的是通过生物信息学分析确定他莫昔芬耐药的潜在机制。方法从Gene Expression Omnibus数据集GSE26459中获取他莫昔芬耐药MCF-7/TR和MCF-7细胞的基因表达谱，用R软件检测差异表达基因（DEGs）。我们使用用于注释、可视化和集成发现的数据库进行了基因本体论 (GO) 和京都基因百科全书和基因组通路富集分析。生成了蛋白质-蛋白质相互作用 (PPI) 网络，我们使用用于检索相互作用基因数据库的搜索工具分析了网络中的中心基因。最后，我们使用 siRNA 沉默靶基因并进行 MTS 测定。结果 我们确定了 865 个 DEG，其中 399 个被上调。GO分析表明，大多数基因与端粒组织、细胞外外泌体和蛋白质异二聚化的结合相关项目有关。PPI 网络构建显示，前 10 个枢纽基因——ACLY、HSPD1、PFAS、GART、TXN、HSPH1、HSPE1、IRAS、TRAP1 和 ATIC——可能与他莫昔芬耐药有关。一致地，RT-qPCR 分析表明，与 MCF-7 细胞相比，这 10 个基因在 MCF-7/TR 细胞中的表达增加。四个中心基因（TXN、HSPD1、HSPH1 和 ATIC）与接受他莫昔芬的患者的总生存期有关。此外，siRNA对HSPH1的敲低可能导致MCF-7/TR细胞生长减少，趋势接近显着性（P = 0.07），表明HSPH1的上调可能在他莫昔芬耐药中起作用。