Abstract

Breast cancer exhibits marked clinical heterogeneity and dynamic epigenetic reprogramming during tumor progression, yet current subtyping approaches fail to capture molecular changes associated with metastasis. Here, we establish a comprehensive biobank of patient-derived organoids (PDOs) from matched primary tumors, adjacent normal tissues, and lymph node metastases. Integrated genomic, transcriptomic, and epigenetic analyses demonstrate that these PDOs preserve tumor-specific molecular signatures and recapitulate epigenetic remodeling during disease evolution. Epigenetic profiling defines four distinct clusters, characterized by unique transcription factor (TF) networks, pathway activities, and therapeutic vulnerabilities not fully represented by conventional classifications. The lymph node metastasis cluster, predominantly comprising metastatic PDOs, displays extensive chromatin remodeling driven by metastasis-enriched TFs, whose depletion markedly impairs spontaneous metastasis in vivo . Together, these findings establish PDO-based epigenetic characterization as a platform for elucidating regulatory mechanisms underlying breast cancer progression and for advancing precision therapeutic strategies.