The CircRNA/miRNA axis in breast cancer: From molecular mechanisms to clinical translation.

Breast cancer remains the second leading cause of cancer-related mortality, with its etiology and pathogenesis involving dysregulated non-coding RNA expression, and the limited efficacy of current targeted therapies underscores an urgent need for novel drug targets and therapeutic modalities. Circular RNAs (circRNAs) are a type of noncoding RNA with a closed loop structure. Emerging evidence suggests that circRNAs function as ceRNAs or miRNA sponges, interact with proteins, and regulate gene transcription and translation. Current research primarily focuses on the ceRNA paradigm, often neglecting issues such as the effective concentration and activity of circRNAs under physiological conditions, as well as the impact of perturbations on individual nodes within complex ceRNA networks. We present a "functional integration" framework. In this model, a pathogenetically validated circRNA molecule serves as an environmentally regulated "molecular toolkit." Under specific pathological conditions, functional modules-such as protein interactions and the encoding of short peptides-can be dynamically activated by multi-level environmental signaling networks to govern phenotypic outputs. When present in a disease-driving circRNA, these modules have the potential to serve as pharmacologically actionable targets, enabling precision interventions-such as small-molecule inhibitors of circRNA-protein interactions, PROTACs targeting oncogenic peptides, and circRNA-based immunotherapies-tailored to the context-dependent primary functional module in each cancer context. This review establishes a foundation for circRNA-based liquid biopsy and therapies targeting specific functional modules.