Leveraging senescence-oxidative stress co-relation to predict prognosis and drug sensitivity in breast invasive carcinoma

Abstract

Introduction: Female breast cancer has risen to be the most common malignancy worldwide, causing a huge disease burden for both patients and society. Both senescence and oxidative stress attach importance to cancer development and progression. However, the prognostic roles of senescence and oxidative stress remain obscure in breast cancer. In this present study, we attempted to establish a predictive model based on senescence-oxidative stress co-relation genes (SOSCRGs) and evaluate its clinical utility in multiple dimensions.

Methods: SOSCRGs were identified via correlation analysis. Transcriptome data and clinical information of patients with breast invasive carcinoma (BRCA) were accessed from The Cancer Genome Atlas (TCGA) and GSE96058. SVM algorithm was employed to process subtype classification of patients with BRCA based on SOSCRGs. LASSO regression analysis was utilized to establish the predictive model based on SOSCRGs. Analyses of the predictive model with regards to efficacy evaluation, subgroup analysis, clinical association, immune infiltration, functional strength, mutation feature, and drug sensitivity were organized. Single-cell analysis was applied to decipher the expression pattern of key SOSCRGs in the tumor microenvironment. Additionally, qPCR was conducted to check the expression levels of key SOSCRGs in five different breast cancer cell lines.

Results: A total of 246 SOSCRGs were identified. Two breast cancer subtypes were determined based on SOSCRGs and subtype 1 showed an active immune landscape. A SOSCRGs-based predictive model was subsequently developed and the risk score was clarified as independent prognostic predictors in breast cancer. A novel nomogram was constructed and exhibited favorable predictive capability. We further ascertained that the infiltration levels of immune cells and expressions of immune checkpoints were significantly influenced by the risk score. The two risk groups were characterized by distinct functional strengths. Sugar metabolism and glycolysis were significantly upregulated in the high risk group. The low risk group was deciphered to harbor PIK3CA mutation-driven tumorigenesis, while TP53 mutation was dominant in the high risk group. The analysis further revealed a significantly positive correlation between risk score and TMB. Patients in the low risk group may also sensitively respond to several drug agents. Single-cell analysis dissected that ERRFI1, ETS1, NDRG1, and ZMAT3 were expressed in the tumor microenvironment. Moreover, the expression levels of the seven SOSCRGs in five different breast cancer cell lines were quantified and compared by qPCR respectively.

Conclusion: Multidimensional evaluations verified the clinical utility of the SOSCRGs-based predictive model to predict prognosis, aid clinical decision, and risk stratification for patients with breast cancer.

Keywords: breast cancer; immune infiltration; oxidative stress; prognosis; senescence; single-cell analysis; tumor mutation burden.