The role of circular RNAs as miRNA sponges in the mechanisms and therapeutic potential of triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast carcinoma which lacks estrogen receptors, progesterone receptors and HER2 along with limited therapeutic options mainly based on chemotherapy. In this review, we outline the emerging function of circRNAs as key regulators in TNBC pathogenesis. CircRNAs are endogenous non-coding RNAs with a closed-loop structure, in contrast to the linear form. In TNBC cells, the underlying molecular mechanism mainly relies on their functions as a competitive sponge of miRNAs, which can absorb or bind to microRNAs (miRNAs) and hence regulate the expression of target genes. Such sponging can result in the activation of oncogenes or repression of tumor suppressor genes, which eventually affect cellular proliferation, apoptosis, and drug sensitivity. Crucial mechanisms include certain circRNAs, such as circEPSTI1, circRAD18, and hsacirc0000199 that enhance tumorigenesis and resistance to chemotherapy by targeting tumor-suppressor miRNAs and activation of oncogenic pathways (e.g., PI3K/Akt/mTOR pathway or Wnt/β-catenin). The potential clinical implications and dysregulation of circRNA-miRNA axes are highlighted, indicating that these may constitute promising diagnostic or prognostic markers by their stability in biofluids. Additionally, this review outlines the innovative treatment approaches regarding these interactions which have recently been addressed and described, novel methods include ASOs therapy, CRISPR/Cas system and nanoplatforms that may help to get over current therapeutic drawbacks in treating TNBC patients.