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.
Highlights
1.7 million women are diagnosed with breast cancer (BC) every year; the disease causes half a million deaths annually worldwide [1,2]
aromatase inhibitors (AIs) are the standard of care in adjuvant-based endocrine therapy in postmenopausal patients [17], while tamoxifen is preferred as adjuvant hormone therapy in the premenopausal setting [13]
Breast cancer stem cells (BCSCs) mediate the recurrence to endocrine therapy, which is in line with the consensus that cancer stem cells (CSCs) are the driving force of cancer evolution and resistance to therapies [31]
Summary
1.7 million women are diagnosed with breast cancer (BC) every year; the disease causes half a million deaths annually worldwide [1,2]. Relapse of ER + ve BCs to hormone therapy is regulated by a complex network, which includes modulations of ER signaling, activation of epidermal growth factor receptor (EGFR) and other growth factor receptors, NOTCH, microenvironmental cues, and others This rich knowledge at the molecular level has yet to translate into the clinic to counter ETR; the resistance remains a major cause of breast cancer fatality. Breast cancer stem cells (BCSCs) mediate the recurrence to endocrine therapy, which is in line with the consensus that cancer stem cells (CSCs) are the driving force of cancer evolution and resistance to therapies [31] In this regard, the aforementioned molecular mechanisms would be converging on regulating BCSCs and thereby lead to ETR.
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