Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
Front Immunol. 2022 Oct 20;13:978909. doi: 10.3389/fimmu.2022.978909. eCollection 2022.
Cuproptosis is a newly discovered programmed cell death dependent on overload copper-induced mitochondrial respiration dysregulation. The positive response to immunotherapy, one of the most important treatments for invasive breast cancer, depends on the dynamic balance between tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). However, cuproptosis-related genes (CRGs) in clinical prognosis, immune cell infiltration, and immunotherapy response remain unclear in breast cancer progression.
The expression and mutation patterns of 12 cuproptosis-related genes were systematically evaluated in the BRCA training group. Through unsupervised clustering analysis and developing a cuproptosis-related scoring system, we further explored the relationship between cuproptosis and breast cancer progression, prognosis, immune cell infiltration, and immunotherapy.
We identified two distinct CuproptosisClusters, which were correlated with the different patterns between clinicopathological features, prognosis, and immune cell infiltration. Moreover, the differences of the three cuproptosis-related gene subtypes were evaluated based on the CuproptosisCluster-related DEGs. Then, a cuproptosis-related gene signature (PGK1, SLC52A2, SEC14L2, RAD23B, SLC16A6, CCL5, and MAL2) and the scoring system were constructed to quantify the cuproptosis pattern of BRCA patients in the training cohort, and the testing cohorts validated them. Specifically, patients from the low-CRG_score group were characterized by higher immune cell infiltration, immune checkpoint expression, immune checkpoint inhibitor (ICI) scores, and greater sensitivity to immunotherapy. Finally, we screened out RAD23B as a favorable target and indicated its expression was associated with breast cancer progression, drug resistance, and poor prognosis in BRCA patients by performing real-time RT-PCR, cell viability, and IC50 assay.
Our results confirmed the essential function of cuproptosis in regulating the progression, prognosis, immune cell infiltration, and response to breast cancer immunotherapy. Quantifying cuproptosis patterns and constructing a CRG_score could help explore the potential molecular mechanisms of cuproptosis regulating BRCA advancement and provide more effective immunotherapy and chemotherapy targets.
铜死亡是一种新发现的依赖于过载铜诱导的线粒体呼吸失调的程序性细胞死亡。免疫治疗是浸润性乳腺癌最重要的治疗方法之一，其对免疫治疗的阳性反应取决于肿瘤微环境（TME）中肿瘤细胞和浸润淋巴细胞之间的动态平衡。然而，在乳腺癌的进展过程中，铜死亡相关基因（CRGs）在临床预后、免疫细胞浸润和免疫治疗反应方面的情况尚不清楚。
系统评估了 BRCA 训练组中 12 个铜死亡相关基因的表达和突变模式。通过无监督聚类分析和建立铜死亡相关评分系统，我们进一步探讨了铜死亡与乳腺癌进展、预后、免疫细胞浸润和免疫治疗的关系。
我们确定了两个不同的 CuproptosisClusters，它们与临床病理特征、预后和免疫细胞浸润的不同模式相关。此外，还基于 CuproptosisCluster 相关 DEGs 评估了三种铜死亡相关基因亚型的差异。然后，构建了一个铜死亡相关基因特征（PGK1、SLC52A2、SEC14L2、RAD23B、SLC16A6、CCL5 和 MAL2）和评分系统，以量化 BRCA 患者在训练队列中的铜死亡模式，并在测试队列中对其进行验证。具体来说，低-CRG_score 组的患者表现出更高的免疫细胞浸润、免疫检查点表达、免疫检查点抑制剂（ICI）评分和对免疫治疗的更高敏感性。最后，我们通过实时 RT-PCR、细胞活力和 IC50 测定筛选出 RAD23B 作为一个有利的靶点，并表明其表达与 BRCA 患者的乳腺癌进展、耐药性和不良预后有关。
我们的研究结果证实了铜死亡在调节乳腺癌的进展、预后、免疫细胞浸润和对免疫治疗的反应方面的重要作用。量化铜死亡模式和构建 CRG_score 可以帮助探索铜死亡调节 BRCA 进展的潜在分子机制，并为更有效的免疫治疗和化疗提供靶点。
