Tang Junjie, Liu Qian, Du Wei, Chen Linxi, Qi Feiyang, Zhang Ranxin, Hoang Bang H, Geller David S, Yang Rui, Wang Jichuan, Hu Li
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Familial & Hereditary Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, China.
The First Clinical Medical School, Nanjing Medical University, Nanjing 211166, China.
Bioengineering (Basel). 2025 May 29;12(6):586. doi: 10.3390/bioengineering12060586.
Parthanatos, a novel form of programmed cell death mediated by PARP1 and driven by DNA damage, has not been comprehensively characterized in breast cancer (BC). Given the widespread clinical use of PARP1 inhibitors for treating BRCA-mutant breast cancers, understanding the role of parthanatos is crucial. In this study, we systematically analyzed the role and clinical significance of parthanatos in BC by integrating genomic, transcriptomic, and clinical data. Our analysis revealed significant differential expression of parthanatos-related genes between BC and normal breast tissues, with frequent copy number variations (CNVs) affecting gene expression. At the single-cell level, parthanatos-related genes were primarily expressed in breast cancer cells and macrophages, and genomic instability scores were positively correlated with parthanatos pathway scores. Unsupervised clustering identified two BC subtypes based on parthanatos-related gene expression: C1 (parthanatos-high) and C2 (parthanatos-low). C1 exhibited a poorer prognosis, reduced immune infiltration, and potential resistance to PARP inhibitors compared to C2. This study represents the first comprehensive investigation of parthanatos in BC, offering insights into its role in tumor progression and highlighting its potential link to PARP inhibitor resistance and poor clinical outcomes.
细胞焦亡是一种由PARP1介导并由DNA损伤驱动的新型程序性细胞死亡形式，在乳腺癌（BC）中尚未得到全面表征。鉴于PARP1抑制剂在治疗BRCA突变型乳腺癌中的广泛临床应用，了解细胞焦亡的作用至关重要。在本研究中，我们通过整合基因组、转录组和临床数据，系统地分析了细胞焦亡在乳腺癌中的作用和临床意义。我们的分析揭示了乳腺癌组织与正常乳腺组织之间细胞焦亡相关基因的显著差异表达，频繁的拷贝数变异（CNV）影响基因表达。在单细胞水平上，细胞焦亡相关基因主要在乳腺癌细胞和巨噬细胞中表达，基因组不稳定性评分与细胞焦亡途径评分呈正相关。无监督聚类基于细胞焦亡相关基因表达确定了两种乳腺癌亚型：C1（细胞焦亡高）和C2（细胞焦亡低）。与C2相比，C1预后较差，免疫浸润减少，对PARP抑制剂可能具有抗性。本研究是对乳腺癌中细胞焦亡的首次全面调查，深入了解了其在肿瘤进展中的作用，并突出了其与PARP抑制剂抗性和不良临床结果的潜在联系。
