Triple-negative breast cancer (TNBC) is the most aggressive and prevalent subtype of breast cancer in women worldwide. Currently, chemotherapy remains the main modality for the treatment at an early stage, as there is no approved targeted therapy for early TNBC. In this review, we investigate the use of microRNAs (miRNAs), which play a key role in the post-transcriptional regulation of genes involved in the key biological processes, namely proliferation, differentiation, angiogenesis, migration, apoptosis, and carcinogenesis. Here, we emphasize the importance of the recent advances related to miRNAs, involving diagnosis, prognosis, and treatment of TNBC. We focus on the development, optimization, and stabilization of miRNA-based drugs; improvement of miRNA delivery; and control of the off-target effects of miRNA therapeutics. We speculate as to which features may present themselves as promising approaches in the treatment of TNBC. Keywords TNBC. miRNA. Cancer biomarkers. miRNA-based therapy Abbreviations Bmi 1 B lymphoma Mo-MLV insertion region 1 homolog CSC Cancer stem cells ER Estrogen receptor HER 2 Human epidermal growth factor receptor 2 PR Progesterone receptor TNBC Triple-negative breast cancer ts-microRNA Tumor suppressor microRNA Highlights • Patients diagnosed with negative ER, PR, and HER 2 are the most prevalent subtypes of breast cancer with limited targeted therapy. • miRNAs play a key role in regulating the gene expression of the key biological processes including proliferation, differentiation, angiogenesis, migration, and apoptosis. The involvement of miRNA has also been identified in carcinogenesis. • In TNBC, miRNAs make major contributions to the diagnosis, prognosis, and treatment. • We suggest that miRNA-based therapeutics could be a promising approach in the treatment of TNBC.

Triple‐negative breast cancer (TNBC) is the most outrageous subtype of breast cancer. Emphasizing the urge of new approach in cancer therapy, combinational drug therapy may be proven as an effective strategy. In our previous study, we reported that coralyne (COR) with paclitaxel (PTX) efficiently decreases the proliferation of MDA‐MB‐231 compared with MCF‐7 cell line. Thus, we studied the effect of COR and PTX in combination on apoptosis of MDA‐MB‐231 cell line. In silico results demonstrated that COR intercalates DNA at a minor groove. In vitro approaches revealed that in combination (COR and PTX) increases the efficacy of apoptosis in MDA‐MB‐231 cell line by a significant increase in G1/S phase arrest, DNA fragmentation, and change in mitochondria membrane potential. The expression of ATM and ATR a serine/threonine‐protein kinase, ataxia telangiectasia and Rad3‐related protein were depleted with an increase in time from 24 to 48 hours in concurrent with increased levels of γH2AX indicating that DNA damage routes cells to enter apoptosis. This was confirmed by high levels of caspase‐3 and cytochrome c. Also, the decrease in the expression levels of matrix metalloproteinase‐9 confirmed the antimetastatic efficacy of COR + PTX. The present study indicates that the synergistic effect of COR and PTX can enhance apoptosis in MDA‐MB‐231 cell line and may be proven as a potential anticancer therapy against TNBC.

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

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Introduction Ionizing radiation (IR) affects healthy tissues during the treatment of cancer radiation therapy and other nuclear and radiological accidents. Some natural compounds showed nonspecific radioprotective activity with severe side effects. The present study is aimed to develop potent and specific radioprotective short hairpin RNA (shRNA), which selectively protects normal cells from IR by specifically targeting matrix metalloproteinases (MMP‐2). Results IR reduced the viability of human normal dermal fibroblasts (HDFs) in a dose‐response manner. It enhanced the expression of MMP‐2 at 10 Gy. Plasmid MMP‐2shRNA (pMMP‐2) reduced the IR (10 Gy) induced cytotoxicity analyzed by lactate dehydrogenase (LDH) assay, normalized IR induced cellular and morphological changes with enhanced the clonogenicity in 48 hours at 2 µg/mL. It reduced the ROS generation, released HDFs from G2/M arrest and rescued from apoptosis analyzed by DCFDA dye, cell cycle analysis by PI stain and annexin V assay, respectively. pMMP‐2 also modulates the expression of EGFR and reduced IR induced expression of DNA damage response protein, ATM and increased the expression of repair proteins, KU70/KU80, and RAD51. In addition, decreased the expression of cell cycle regulatory proteins cyclin‐dependent kinases (CDK1) and Cyclin B as well as proapoptotic proteins BAX, caspase‐3, and Cytochrome‐C and increased the expression of survival protein, Bcl‐2. In contrary pMMP‐2 decreased the LDH activity, survival fraction and blocked G2/M phase of cell cycle and increased apoptosis in MCF‐7 cells. In addition, decreased the expression of EGFR, proapoptotic BAX and DNA repair proteins ATM, KU70/80 and RAD51, increased expression of cyclinB as well as CDK1. Conclusion Results conclude that pMMP‐2 protected HDFs from IR and sensitized the MCF‐7 cells. Therefore, pMMP‐2 can be employed for better treatment of radiation accidents and during the treatment of radiotherapy.