Breast cancer stem cells: Biological roles, microenvironmental interactions, and therapeutic targeting

Breast cancer stem cells (BCSCs) represent a small but critical subpopulation within breast tumors that drive tumor initiation, progression, metastasis, therapeutic resistance, and recurrence. BCSCs are characterized by cell surface markers such as CD44⁺/CD24⁻ and high aldehyde dehydrogenase 1 (ALDH1) activity, and are regulated by pluripotency-associated transcription factors including POU class 5 homeobox 1 (OCT4), SRY-Box transcription factor 2 (SOX2), and Nanog homeobox (NANOG). They exhibit remarkable plasticity and heterogeneity across different breast cancer subtypes, which is further enhanced by epithelial-mesenchymal transition and dynamic interactions with the tumor microenvironment, enabling immune evasion and adaptation to hostile conditions such as hypoxia. Functionally, BCSCs sustain tumorigenesis through self-renewal, contribute to metastatic dissemination as circulating tumor cells, and can enter dormancy in distant niches, leading to late recurrences. Their intrinsic resistance to chemotherapy, radiotherapy, and targeted therapies arises from quiescence, enhanced DNA damage repair, overexpression of drug efflux transporters, and metabolic reprogramming, posing major clinical challenges. Recent advances have improved BCSC identification and isolation through marker-based cell sorting, dye exclusion assays, mammosphere culture, and functional reporter systems. Conventional therapies often spare or enrich BCSCs, highlighting the need for novel treatments. Targeted strategies focusing on stemness-related signaling pathways such as Wnt, Notch, and Hedgehog, as well as regulators including NANOG, ALDH1 and programmed death-ligand 1 (PD-L1), are under investigation. Emerging approaches incorporating natural compounds, nanotechnology, and microenvironmental modulation show promise in overcoming therapeutic resistance. This review integrates current understanding of BCSC biology, heterogeneity, and microenvironmental interactions, providing valuable insights for breast cancer.