Multi-Omics Profiling Identifies a High-Risk Subgroup of Breast Cancer Stem Cells for Prognostic Stratification and Personalized Treatment

<b>Background:</b> Breast cancer is the most prevalent malignancy among females worldwide. Extensive research has highlighted cancer stem cells (CSCs) as critical drivers of tumor initiation, progression, recurrence, and therapy resistance. However, the heterogeneity of breast cancer stem cells (BCSCs) and their dynamic roles within the tumor microenvironment remain inadequately understood. <b>Methods:</b> This study utilized the single-cell RNA sequencing dataset to categorize BCSCs into two subgroups within the breast cancer microenvironment and investigate their pseudo-time developmental dynamics. Bulk transcriptomic data from TCGA-BRCA were integrated to assess the prognostic significance and infiltration abundance of the BCSCs-2 subgroup. Functional enrichment, co-expression network analysis, and somatic mutation profiling were performed to elucidate key biological pathways and genetic features. Additionally, drug sensitivity analyses were conducted using the Connectivity Map database to identify potential therapeutic strategies. <b>Results:</b> A total of 459 BCSCs were identified and further classified into two distinct subpopulations: BCSCs-1 and BCSCs-2. High infiltration of BCSCs-2 was associated with poor prognosis and an immunosuppressive tumor microenvironment. Co-expression network analysis identified 16 key genes linked to BCSCs-2, while somatic mutation analysis revealed distinct mutation patterns associated with its infiltration. Drug sensitivity analysis suggested that patients with high BCSCs-2 infiltration could benefit from classical chemotherapy agents, such as Cisplatin, and other novel therapeutic compounds. <b>Conclusions:</b> This study offers novel insights into the heterogeneity and functional roles of BCSCs in breast cancer. The findings highlight the prognostic and therapeutic importance of the BCSCs-2 subgroup, providing potential biomarkers and therapeutic targets for precision medicine in breast cancer management.