The PDGFB–DDX5 axis contributes to breast cancer radioresistance through HR-associated DNA repair

Radioresistance remains a major barrier to effective breast cancer treatment, yet the molecular programs underlying acquired resistance remain incompletely understood. By establishing and characterizing radioresistant breast cancer cell models across multiple molecular subtypes, we revealed enhanced DNA repair capacity and epithelial-mesenchymal transition features in resistant cells. Transcriptomic profiling and functional validation identified platelet-derived growth factor B (PDGFB) as a key regulator of radioresistance. High PDGFB expression was associated with adverse outcomes across independent breast cancer cohorts, including a radiotherapy-treated subgroup. Mechanistically, PDGFB associated with DEAD-box RNA helicase 5 (DDX5) and stabilized DDX5 by limiting its ubiquitin-proteasome-mediated degradation. PDGFB depletion impaired homologous recombination (HR) efficiency, delayed DNA damage resolution, reduced RAD51 foci formation, and resensitized radioresistant cells to irradiation in vitro and in vivo. Conversely, DDX5 overexpression partially restored HR signaling, DNA damage resolution, and clonogenic survival in PDGFB-depleted cells. These findings uncovered a PDGFB-DDX5 regulatory axis that preferentially targets homologous recombination-associated DNA repair and contributes to breast cancer radioresistance. Implications: This study demonstrates the PDGFB–DDX5 axis as a crucial mechanism contributing to radioresistance by preferentially affects HR–mediated DNA damage repair, which can be therapeutically explored for overcoming radioresistance in breast cancer.