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

Target-directed microRNA degradation (TDMD) influences cell states and therapy resistance in breast cancer, with 19 key substrates identified, including miR-29b-3p and miR-33a/b-5p.

• Why it matters: Understanding miRNA turnover mechanisms is crucial because they regulate gene expression and cellular plasticity, impacting cancer progression and treatment outcomes.
• What they did: The study used CRISPRi-mediated ZSWIM8 depletion, miRNA sequencing, and AGO2-eCLIP to map TDMD across breast cancer subtypes, revealing both canonical and non-canonical pathways involving specific transcripts.
• The result: Findings show TDMD shapes tumor cell states, promotes stem-like properties, and confers drug resistance, providing insights into miRNA regulation that could inform targeted therapies for aggressive breast cancers.