ADAM and ADAMTS Proteases in Breast Cancer: Molecular Mechanisms and Therapeutic Implications.

Breast cancer ranks as the second most significant cause of cancer-related mortality on a global scale, with its incidence demonstrating a continual upward trajectory. Investigating gene targets for cancer therapies has advanced through innovative methodologies focusing on genes and pathways driving cancer progression. A disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs) constitute related protease families, with ADAMs primarily functioning as membrane-anchored cell-surface enzymes and ADAMTSs secreted into the extracellular matrix. These proteases drive oncogenic signaling via ectodomain shedding of growth factors and receptors, modulating EGFR, PI3K/AKT/mTOR, TNF-α, Notch, and JAK-STAT pathways. ADAM10 and ADAM17 particularly promote breast cancer invasion and metastasis in HER2-positive and triple-negative subtypes, establishing them as biomarkers and therapeutic targets. Conversely, certain ADAMTS members exhibit tumor-suppressive functions by inhibiting angiogenesis and ECM remodeling. Regulatory cofactors such as iRhom proteins modulate ADAM17 maturation and substrate selectivity, adding complexity to this proteolytic network. This review synthesizes recent advances in ADAMs/ADAMTs in breast cancer, highlighting roles in promoting or suppressing tumorigenesis depending on isoform and molecular context. Multiple therapeutic modalities have been validated, including small-molecule inhibitors (INCB7839, INCB3619, GI254023X) that suppress ligand shedding and enhance trastuzumab efficacy, RNA interference (siRNA/miRNA) for targeted gene silencing, and engineered nanocarrier drug delivery platforms that overcome therapeutic resistance. The epigenetic regulation, post-translational modifications, and diagnostic advancements, such as SERS-based serum profiling, further underscore their value as biomarkers and druggable targets. Collectively, ADAM/ADAMTS-centered interventions represent a promising direction for precision oncology and therapeutic targets for improving clinical outcomes in breast cancer.