The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

Abstract

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities

“…From a clinical point of view, the ability of non-stem cancer cells to acquire BCSCs properties and, in general, the plasticity of the BCSC compartment pose a serious challenge to targeted therapeutic strategies. In fact, targeting a specific population of BCSCs (such as ER-positive BCSCs in ER + BC) often results in disappearance of the therapeutic target or acquisition of resistance through alternative signalling pathways [34]. The SWH/HIPPO (Salvador-Warts-Hippo) pathway has been reported to play a central role in the transition towards a stem cell state in BC, as a gain of the PDZ-binding motif (TAZ) confers self-renewal capacity and BCSCs features to non-stem BC cells [35].…”

Notch Signaling in Breast Cancer: A Role in Drug Resistance

“…Though targeted therapies are efficacious in non-advanced disease, a reported 20–50% of HER2+ metastatic tumors have an inherent resistance to trastuzumab or other HER2-targeted agents, and 10–15% will acquire resistance within the first year of treatment [ 10 , 19 , 20 ]. Similarly, 30% of ER+ tumors display intrinsic resistance to one or more forms of endocrine therapy, and approximately 30% acquire resistance to tamoxifen [ 21 ]. Triple negative breast cancers are inherently resistant to HER2 or ER-targeted therapies and thus are treated with cytotoxic chemotherapy, such as taxane-based, platin-based, and other DNA-damaging agents [ 22 ].…”

Slug and E-Cadherin: Stealth Accomplices?

“…Despite controversies surrounding the cancer stem cell (CSC) theory, the concept has contributed to the identification of cancer cell plasticity and important mechanisms underlying tumor progression (Wang et al, 2015 ). Various cell surface molecules (e.g., CD44, CD24, CD133) and combinations thereof as well as ALDH activity have been used to enrich for cells with stemness properties and their frequency varies by BC subtype (Rodriguez et al, 2019 ). The CD44 + /CD24 −/low CSCs are mesenchymal-like while ALDH1 + and CD44 + /CD24 + stem cells are epithelial-like.…”