Abstract
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.
Highlights
Counteracting therapeutic resistance remains a key challenge that determines the efficacy of cancer treatment and the overall outcome and impact of the disease in the lives of affected individuals
We have detailed how breast cancer stem cells (BCSCs) contribute to drug/therapeutic resistance in breast cancers and discussed how targeting the various aspects of BCSC conferred drug/therapeutic resistance could in turn sensitize breast cancers to therapeutic intervention and prevent relapse/recurrence of the disease
The current data available on the anti-neoplastic effects of metformin makes it an interesting candidate for drug re-purposing for the treatment of cancers
Summary
Once considered as a pathological condition stemming from the dysregulation of proliferation and apoptosis caused by gene mutations, has gained importance as a metabolic, inflammatory, and lifestyle disease, which can be caused by infectious agents (bacteria and viruses) [29,30,31,32,33]. Random variations in the expression of oncogenes and tumor suppressor genes in response to exposure to anti-cancer therapeutic interventions result in the enrichment of therapy-resistant variant cells in the tumor and the development of ‘acquired’ resistance to therapeutic intervention [21,34]. In cancers, including breast cancers, the factors that influence therapeutic resistance mainly include (Figure 1): (1) the presence of breast cancer stem cells (BCSCs), (2) epithelial–mesenchymal transition, (3) tumor heterogeneity and microenvironment, (4) active DNA damage repair mechanisms, (5) altered/adaptive/aberrant metabolism, (6) variations in drug uptake and active drug efflux systems, (7) activation of oncogenic, pro-survival, and anti-apoptotic signaling pathways, and (8) active drug detoxification and target alteration systems [21,34]. Similar mechanisms, in the perspective of BCSCs, which confer resistance to breast cancer against therapeutic intervention, are explained in Section 4 (role of BCSCs in chemoresistance in breast cancers) below
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