Circular RNAs in Breast Cancer Progression and their Potential Clinical Applications

Breast cancer (BC) is the most prevalent malignant tumor among women globally. It is a biologically heterogeneous disease driven by complex genetic and epigenetic alterations that influence tumor initiation, progression, metastasis, and therapeutic response. Among the epigenetic regulators, non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and circular RNAs (circRNAs), have emerged as key modulators of BC biology through intricate regulatory networks. CircRNAs are endogenous RNA molecules generated by back-splicing of precursor messenger RNAs, forming covalently closed-loop structures that confer remarkable stability and resistance to exonuclease-mediated degradation. Although initially identified in the 1970s, their biological significance became evident following advances in high-throughput RNA sequencing and bioinformatics, which revealed their widespread expression and diverse regulatory functions. CircRNAs modulate gene expression by acting as competing endogenous RNAs that sponge miRNAs, interacting with RNA-binding proteins, regulating parental gene transcription, and, in some cases, encoding functional peptides. Through these mechanisms, they regulate essential cellular processes, including proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition, metastasis, and therapeutic resistance. Accumulating evidence demonstrates that aberrant circRNA expression is closely associated with clinicopathological characteristics, molecular subtypes, treatment response, and patient prognosis in BC. Owing to their high stability, tissue specificity, and detectability in body fluids, circRNAs have emerged as promising non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring. Furthermore, advances in RNA-based therapeutics have highlighted circRNAs as attractive therapeutic targets through approaches such as engineered circRNAs, antisense oligonucleotides, RNA interference, and CRISPR/Cas13-mediated strategies. This review summarizes circRNA biogenesis, functions, and regulatory mechanisms, particularly circRNA/miRNA/mRNA axes, and explores their roles in BC progression, drug resistance, and potential clinical applications as biomarkers and therapeutic targets in precision oncology.