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

by David Rodriguez 1,2,3,4,†, Marc Ramkairsingh 1,2,3,4,†, Xiaozeng Lin 1,2,3,4, Anil Kapoor 2,3,5, Pierre Major 6 and Damu Tang 1,2,3,4,*
1
Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
2
The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
3
Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
4
The Hamilton Center for Kidney Research, St. Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
5
Department of Surgery, McMaster University, Hamilton, Hamilton, ON L8S 4K1, Canada
6
Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, ON, L8V 5C2, Canada
*
Author to whom correspondence should be addressed.
Equal contributions.
Cancers 2019, 11(7), 1028; https://doi.org/10.3390/cancers11071028
Received: 22 June 2019 / Revised: 17 July 2019 / Accepted: 17 July 2019 / Published: 22 July 2019
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. View Full-Text
Keywords: ER-positive breast cancer; endocrine therapy resistance; breast cancer stem cells; hormone and growth factor signaling; microenvironment ER-positive breast cancer; endocrine therapy resistance; breast cancer stem cells; hormone and growth factor signaling; microenvironment
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Rodriguez, D.; Ramkairsingh, M.; Lin, X.; Kapoor, A.; Major, P.; Tang, D. The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer. Cancers 2019, 11, 1028.

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