Excavating regulated cell death signatures to predict prognosis, tumor microenvironment and therapeutic response in HR+/HER2- breast cancer

Regulated cell death (RCD) has been documented to have great potentials for discovering novel biomarkers and therapeutic targets in malignancies. But its role and clinical value in HR+/HER2- breast cancer, the most common subtype of breast cancer, are obscure. In this study, we comprehensively explored 12 types of RCD patterns and found extensive mutations and dysregulations of RCD genes in HR+/HER2- breast cancer. A prognostic RCD scoring system (CDScore) based on six critical genes (LEF1, SLC7A11, SFRP1, IGFBP6, CXCL2, STXBP1) was constructed, in which a high CDScore predicts poor prognosis. The expressions and prognostic value of LEF1 and SFRP1were also validated in our tissue microarrays. The nomogram established basing on CDScore, age and TNM stage performed satisfactory in predicting overall survival, with an area under the ROC curve of 0.89, 0.82 and 0.8 in predicting 1-year, 3-year and 5-year overall survival rates, respectively. Furthermore, CDScore was identified to be correlated with tumor microenvironments and immune checkpoints by excavation of bulk and single-cell sequencing data. Patients in CDScore high group might be resistant to standard chemotherapy and target therapy. Our results underlined the potential effects and importance of RCD in HR+/HER2- breast cancer and provided novel biomarkers and therapeutic targets for HR+/HER2- breast cancer patients.