Novel miRNA Targets and Therapies in the Triple-Negative Breast Cancer Microenvironment: An Emerging Hope for a Challenging Disease

Abstract

Treatment of triple-negative breast cancer (TNBC) remains challenging because of the heterogeneity of the disease and lack of single targetable driving mutations. TNBC does not rely on estrogen, progesterone or epidermal growth factor receptors and is associated with aggressive disease progression and poor prognosis. TNBC is also characterized by resistance to chemotherapeutics, and response to immunotherapies is limited despite promising results in a subset of TNBC patients. MicroRNAs (miRNAs) have emerged as significant drivers of tumorigenesis and tumor progression in triple-negative breast cancer (TNBC) and present unique opportunities to target various components of the TNBC microenvironment for improved efficacy against this difficult to treat cancer. Effects of miRNAs on multiple targets may improve response rates in the context of this genetically and biologically heterogeneous disease. In this review, we offer a comprehensive view of miRNA regulation in TNBC, treatment challenges presented by TNBC in the context of the tumor microenvironment and stem cell subpopulations, and current and emerging miRNA-based therapeutic strategies targeting various components of the TNBC microenvironment. In addition, we offer insight into novel targets that have potential for treating TNBC through multiple mechanisms in the tumor microenvironment simultaneously and those that may be synergistic with standard chemotherapies.

Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)

“…This binding either degrades mRNA or represses translation ( 154 ). miRNA is a key player in tumorigenesis, stemness, and drug resistance in TNBC ( 155 – 157 ). For instance, tumour suppressor miRNAs, involved in tumour development, miR-190a, miR-136-5p, miR-126-5p, miR-135b-5p and miR-182-5p are downregulated in TNBC ( 158 ).…”

Immune Classification and Immune Landscape Analysis of Triple-Negative Breast Cancer

“…The TIME refers to the complex network of internal and external environments for the occurrence, growth, and metastasis of tumors, including tumor cells, immune molecules, extracellular matrix, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and other immune-related cells ( Malone et al, 2020 ; Qattan, 2020 ). On the one hand, innate and acquired immune responses mediated by immune cells and molecules can eliminate tumor cells to inhibit tumor emergence.…”

“…TILs are frequently detected in BC, especially in TNBC, suggesting richer immune infiltration and more significant immunogenicity. A large amount of clinical data has proven that the number of TILs is significantly positively correlated with the expected survival of TNBC patients and is an independent biomarker for patient prognosis ( Park et al, 2018 ; Qattan, 2020 ). In 2019, the WHO officially listed TILs as one of the biomarkers for the clinicopathological analysis of BC ( Blackley and Loi, 2019 ).…”

MicroRNA-1246 Mediates Drug Resistance and Metastasis in Breast Cancer by Targeting NFE2L3

“…Recently, an increasing number of studies have focused on non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miRNAs are small non-coding RNAs containing ~22 nucleotides, which can negatively regulate the expression of genes by binding to the 3’-untranslated region (3’-UTR) of their target mRNAs ( 5 ). Accumulating evidences have indicated that miRNAs played important roles in the regulation of cell proliferation, apoptosis, migration, invasion, and metabolism ( 6 ).…”