Effects of nucleic acid metabolism on prognosis and immune invasion of triple-negative breast cancer

Abstract

The nucleic acid metabolism process is driven by various carcinogenic factors, providing a material basis and energy guarantee for the malignant phenotype of tumor cells. However, the role of nucleic acid metabolism in triple-negative breast cancer (TNBC) development remains unclear. Here, we examined the expression patterns of nucleic acid metabolism-related genes (NAMRGs) in the transcriptome of 297 TNBC samples derived from three datasets. We used single-cell RNA sequencing analysis and both in vivo and in vitro experiments to verify the correlation between NAMRGs and tumor metastasis and tumor immune matrix microenvironment (TME) characteristics. According to the results, two different molecular subtypes were identified, and the relationships between the molecular subtypes, four genetic subtypes, and four pathological subtypes were established. Changes in nucleic acid metabolism were related to changes in homologous recombination repair defects (HRD), cell infiltration in the TME, and patient prognosis. We also constructed a prediction model, NAM_model, by including four NAMRGs (DPYD, PDE6G, PDE8B, and TYMS) and integrating it with other clinical indicators. This model was a highly accurate prognostic nomogram, which showed that the prognosis of high-risk patients was poor, with NAMRGs associated with TME immune exhaustion. In addition, NAMRGs were significantly correlated with drug sensitivity to chemotherapy and targeted therapy. In vivo and in vitro studies have shown that PDE8B is an oncogene that promotes tumor growth and induces TNBC metastasis by promoting epithelial-mesenchymal transition (EMT), which has not been reported previously. Single-cell RNA sequencing also revealed the unique effects of nucleic acid metabolism and HRD on exhausted CD8+ T cells. A comprehensive analysis of NAMRGs revealed the potential impact of nucleic acid metabolism-mediated mechanisms, such as HRD and EMT, on the clinical pathological characteristics, TME characteristics, and prognosis of patients with TNBC. These findings have deepened our understanding of the roles of NAMRGs in TNBC and immunotherapy, which will greatly contribute to patient stratification management and individualized clinical decision-making.