Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications

SIMPLE SUMMARY: Cancer stem cells (CSCs) in breast cancer have been identified for almost two decades. Many outstanding discoveries have established the important functions of CSCs in breast cancer progression, metastasis, and resistance to therapy. As the defining feature of CSCs, stemness is induced and maintained by several important signaling pathways. Targeting these pathways is inevitably challenging because they are also critically involved in normal stem cells. Here, we will summarize the literature on breast cancer stem cells, including major signaling pathways, cellular interactions within the tumor microenvironment (TME), and potential therapeutic implications. ABSTRACT: Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.