Construction and validation of predictive model based on endoplasmic reticulum stress-related genes for triple-negative breast cancer

Triple-negative breast cancer (TNBC) poses challenges in treatment due to its inherent biological characteristics. Endoplasmic reticulum stress (ERS) has been associated with the development of TNBC. Hence, identifying ERS-related prognostic biomarkers is crucial for the early diagnosis and treatment of TNBC. In this study, we retrieved gene expression profiles from TNBC patients using The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) between TNBC tumor and normal tissues were identified using limma package. Using differential expression analysis, we identified 46 ERS-related DEGs. Through univariate Cox, LASSO, and multivariate COX regression analyses, we constructed a prognostic model consisting of 8 genes (IGFBP1, CFTR, THBS4, CREBRF, CLU, HDGF, DERL3, NCCRP1). This model demonstrated robust prognostic accuracy in TNBC patients, validated by the METABRIC dataset. Among the 8 prognostic genes, NCCRP1 showed the highest expression increase in BT-20 and MDA-MB-468 cells. Functional assays further revealed that NCCRP1 significantly promoted proliferation, migration, and invasion, while suppressing apoptosis and ERS in these TNBC cell lines. Our study highlights a strong association between ERS-related genes and the prognosis of TNBC patients. Moreover, we demonstrated that NCCRP1 exerts oncogenic effects in TNBC cells. It provides new insights and possible treatment targets for TNBC.

三阴性乳腺癌（Triple-negative breast cancer, TNBC）因其固有的生物学特性，临床治疗颇具挑战。内质网应激（Endoplasmic reticulum stress, ERS）与三阴性乳腺癌的发生发展密切相关，因此筛选内质网应激相关的预后生物标志物，对三阴性乳腺癌的早期诊断与治疗至关重要。本研究从癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中获取三阴性乳腺癌患者的基因表达谱数据，采用limma软件包鉴定三阴性乳腺癌肿瘤组织与正常组织间的差异表达基因（Differentially expressed genes, DEGs），经差异表达分析共筛选得到46个内质网应激相关差异表达基因。通过单因素Cox、最小绝对收缩与选择算子（LASSO）及多因素Cox回归分析，本研究构建了由IGFBP1、CFTR、THBS4、CREBRF、CLU、HDGF、DERL3、NCCRP1这8个基因组成的预后预测模型。该模型在三阴性乳腺癌患者中展现出稳健且优异的预后预测效能，经METABRIC数据集验证其稳定性与准确性。在这8个预后相关基因中，NCCRP1在BT-20与MDA-MB-468细胞系中的表达上调幅度最为显著。功能实验进一步证实，NCCRP1可显著促进三阴性乳腺癌细胞的增殖、迁移与侵袭能力，同时抑制细胞凋亡与内质网应激过程。本研究揭示了内质网应激相关基因与三阴性乳腺癌患者预后的紧密关联，并证实NCCRP1在三阴性乳腺癌细胞中发挥致癌作用，为三阴性乳腺癌的诊疗提供了全新的研究思路与潜在治疗靶点。