Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance

Abstract

Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.

High expression of cuproptosis-related SLC31A1 gene in relation to unfavorable outcome and deregulated immune cell infiltration in breast cancer: an analysis based on public databases

“…Patients with human epidermal growth factor 2 (HER2)-positive advanced breast cancer expected a median PFS of 18.5 months in the era of HER2-targeted agents trastuzumab and pertuzumab [9,10]. However, immunotherapy and targeted therapy were greatly limited by low response rates, lack of effective response predictors, resistance as well as drug toxicity [11][12][13]. In this context, therapies which could induce alternate forms of regulated cell death, ferroptosis, pyroptosis, necroptosis and apoptosis, for instance, become potential strategies to eliminate resistant breast cancer cells and improve survival [11].…”

“…However, immunotherapy and targeted therapy were greatly limited by low response rates, lack of effective response predictors, resistance as well as drug toxicity [11][12][13]. In this context, therapies which could induce alternate forms of regulated cell death, ferroptosis, pyroptosis, necroptosis and apoptosis, for instance, become potential strategies to eliminate resistant breast cancer cells and improve survival [11].…”

Visualization system based on hierarchical targeting for diagnosis and treatment of hepatocellular carcinoma

“…As a traditional cancer treatment modality, chemotherapy alone can inhibit tumor growth to a certain extent [ 51 ]. However, most chemotherapeutic agents have suboptimal accumulation barriers [ 52 ]; these severely impede clinical treatment when combined with tumor resistance [ 5 , 51 ]. We designed a graded targeting multifunctional system that significantly improved drug enrichment in tumor tissues through primary targeting, solving the above-mentioned limitations effectively.…”

“…However, the enrichment rate of drugs or contrast agents in the target region is poor owing to the complex environment of the human body [ 4 ], which makes it impossible to diagnose and treat tumors efficiently at the molecular level. The low drug enrichment rate and high drug resistance of tumor cells, especially the high drug resistance of cancer stem cells (CSCs), also decrease the efficiency of the clinical drug treatment [ 5 , 6 ]. Recently, targeted drug delivery has gained attention as an effective strategy for precision therapy [ [7] , [8] , [9] ].…”

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

“…CSCs have been recognized as the main cause of drug resistance, metastasis, and recurrence of cancer (166,167). Growing evidence suggests that miRNAs are involved in cancer drug resistance by altering the characteristics of CSCs (168). For instance, Zhang et al found that miR-132 was upregulated in the Lrg5 + gastric CSCs isolated from MKN45 and MKN28 cells.…”