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Entosis: From Cell Biology to Clinical Cancer Pathology
Review

Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

1
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
2
Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
3
Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
*
Authors to whom correspondence should be addressed.
Received: 26 July 2020 / Revised: 19 August 2020 / Accepted: 22 August 2020 / Published: 1 September 2020
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting. View Full-Text
Keywords: cancer; cancer stem cells; chemoresistance; metformin; multidrug resistance cancer; cancer stem cells; chemoresistance; metformin; multidrug resistance
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MDPI and ACS Style

Samuel, S.M.; Varghese, E.; Koklesová, L.; Líšková, A.; Kubatka, P.; Büsselberg, D. Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells. Cancers 2020, 12, 2482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092482

AMA Style

Samuel SM, Varghese E, Koklesová L, Líšková A, Kubatka P, Büsselberg D. Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells. Cancers. 2020; 12(9):2482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092482

Chicago/Turabian Style

Samuel, Samson M., Elizabeth Varghese, Lenka Koklesová, Alena Líšková, Peter Kubatka, and Dietrich Büsselberg. 2020. "Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells" Cancers 12, no. 9: 2482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092482

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