Identification of DDIT4 as a Potential Prognostic Marker Associated with Chemotherapy and Immunotherapy Response in Triple-Negative Breast Cancer

Abstract Background Triple-negative breast cancer (TNBC) is the most heterogenous and aggressive subtype of breast cancer. Chemotherapy remains the standard treatment option for patients with TNBC owing to the unavailability of acceptable targets and biomarkers in clinical practice. Novel biomarkers and targets for patient stratification and treatment of TNBC are urgently needed. In this study, we aimed to identify novel biomarkers and therapeutic targets using RNA sequencing (RNA-seq) and data mining using data from public databases. Methods RNA-sequencing (RNA-Seq) was performed to detect the different gene expression patterns in the human TNBC cell line HS578T treated with docetaxel or doxorubicin. Raw data were analyzed using the R package “edgeR” to identify the profile of differentially expressed genes (DEGs) and functionally annotated through R package “clusterProfiler.” The prognostic and predictive value of DNA damage-inducible transcript 4 gene (DDIT4) expression in patients with TNBC was further studied using published online data resources, including TIMER, UALCAN, and Kaplan-Meier Plotter. LinkedOmics and GeneMANIA were used to investigate the genes and functional networks related to DDIT4. GSCALite was used to analyze the pathway activities of DDIT4 and its hub genes. Results Through the integrative analyses of RNA-Seq data and public datasets, we observed the overexpression of DDIT4 in TNBC tissues(p<0.01) and found that patients with DDIT4 overexpression showed poor survival outcomes (p<0.05). Notably, immune infiltration analysis showed that the levels of DDIT4 expression correlated negatively with the abundance of tumor-infiltrating immune cells and immune biomarker expression (p<0.05), but correlated positively with immune checkpoint molecules (p<0.01). Furthermore, DDIT4 and its hub genes (ADM, ENO1, PLOD1, and CEBPB) involved in the activation of Apoptosis, Cell Cycle and EMT pathways. Eventually, we found ADM, ENO1, PLOD1 and CEBPB showed poor overall survival in BC patients (p<0.01). Conclusion In this study, we found that DDIT4 expression is associated with the progression, therapeutic efficacy, and immune microenvironment of patients with TNBC, and DDIT4 would be as a potential prognostic biomarker and therapeutic target. These findings will help to identify potential new molecular targets and improve therapeutic strategies against TNBC.