Canonical and non-canonical miRNA degradation shapes state transitions and stemness in breast cancer.

Target-directed microRNA degradation (TDMD) influences cellular states and therapy resistance in breast cancer, with 19 substrates identified, including miR-29b-3p and miR-30c-5p.

• Why it matters: Understanding miRNA turnover mechanisms like TDMD is crucial because they regulate gene expression and may impact cancer progression and treatment responses, yet their roles in human cancers are not well characterized.
• What they did: The study used CRISPRi-mediated ZSWIM8 depletion, miRNA-seq, and AGO2-eCLIP to map TDMD across breast cancer subtypes, identifying key substrates and mechanisms, including a non-canonical pathway.
• The result: Findings show TDMD shapes miRNA target occupancy and repression, with miR-29b-3p TDMD linked to stem-like, tumor-initiating cells, and non-canonical miR-30c-5p degradation associated with paclitaxel resistance, highlighting its role in cancer cell plasticity and therapy response.