Abstract
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.