CircRNA/miRNA axis in breast cancer offers novel therapeutic targets and liquid biopsy potential

Breast cancer remains a leading cause of cancer mortality, with current targeted therapies often showing limited efficacy due to molecular heterogeneity. This underscores an urgent need for novel drug targets and therapeutic modalities. Dysregulated non-coding RNA expression, particularly circular RNAs (circRNAs), is implicated in its etiology and pathogenesis. CircRNAs, with their closed-loop structure, function as ceRNAs or miRNA sponges, interact with proteins, and regulate gene transcription, presenting a promising avenue for intervention.

This review synthesizes emerging evidence on circular RNAs (circRNAs) in breast cancer, moving beyond the predominant ceRNA paradigm. Researchers analyzed studies on circRNA function, including their roles as miRNA sponges, protein interactors, and regulators of gene transcription and translation. The authors then developed a novel 'functional integration' framework, which posits that pathogenetically validated circRNAs act as environmentally regulated 'molecular toolkits' to dynamically activate functional modules under specific pathological conditions.

The review highlights that circRNAs are not merely miRNA sponges but possess diverse functions, including direct protein interactions and encoding short peptides. A key finding is the proposed 'functional integration' framework, where a disease-driving circRNA can serve as an environmentally regulated 'molecular toolkit.'

Under specific pathological conditions, functional modules within these circRNAs—such as protein interaction domains or peptide-encoding sequences—can be dynamically activated by multi-level environmental signaling networks to govern phenotypic outputs. These modules represent potential pharmacologically actionable targets. Examples include small-molecule inhibitors targeting circRNA-protein interactions, PROTACs designed to degrade oncogenic peptides encoded by circRNAs, and novel circRNA-based immunotherapies. This context-dependent targeting allows for precision interventions tailored to the primary functional module driving cancer in each specific case.