Breast cancer: miRNAs monitoring chemoresistance and systemic therapy

Abstract

With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.

Keywords: breast cancer; chemoresistance; micro RNA; neoadjuvant (chemo)radiotherapy; systemic therapies.

Figure 1

The major chemoresistance mechanisms of cancer cells.

Figure 2

MiRNA expression and function. RNA polymerase II enzyme in the nucleus transcribes the miRNA-encoding genes, forming the “Pri-miRNA” hairpin-shaped molecule. DROSHA and DGCR8 molecules work together to transform the “Pri-miRNA” molecule into the “Pre-miRNA” precursor molecule. Pre-miRNA then travels to the nuclear export receptor “Exportin 5” and reaches the cytoplasm. This precursor is cleaved by Dicer complex in the cytoplasm to create a double-stranded molecule called “miRNA duplex.” One of these two strands is left active after this process, and it has the ability to suppress or even activate the target downstream genes at the transcriptional or translational level.

Figure 3

Schematic representation of miRNAs involved in drug resistance through regulating (A) cell cycle, (B) DNA repair checkpoints, (C) cell death, and (D) stemness and epithelial to mesenchymal transition. A line with a perpendicular line at the end designates inhibition and arrows designate activation. miRNAs increasing drug resistance are shown in red, and miRNAs increasing drug sensitivity are shown in green. CIS, cisplatin; DOX, doxorubicin; DTX, docetaxel; FUL, fulvestrant; PTX, paclitaxel; TAM, tamoxifen; TRA, trastuzumab; 5-FU, 5-fuorouracil; CPT, camptothecin; ETO, etoposide; MNNG, N-methylN′-nitro-N-nitrosoguanidine; PARPi, PARP inhibitors; RAD, radiation; TMZ, temozolomide; EPB, epirubicin; GCB, gemcitabine.

Figure 4

Figure showing how miRNA expression profiles can be altered for cancer treatment.

Figure 5

Types of microRNA delivery techniques employed in cancer therapy.

Figure 6

Challenges in miRNA delivery.