Progress for RAD18's mechanism in breast cancer radioresistant

Radioresistance remains a critical barrier to achieving durable locoregional control and improved survival outcomes in breast cancer. RAD18, an E3 ubiquitin ligase that regulates translesion synthesis and post-replication repair, has emerged as a candidate mediator of this phenotype by promoting proliferating cell nuclear antigen (PCNA) ubiquitination, facilitating replication stress tolerance, and enabling tumor cell survival following DNA damage. In parallel, the PI3K/AKT/mTOR (PAM) signaling pathway represents one of the most frequently dysregulated oncogenic networks in breast cancer and is increasingly recognized as a central determinant of therapeutic resistance. Notably, however, its biological and clinical relevance is highly context-dependent, with the strongest evidence observed in hormone receptor-positive (HR+)/HER2-negative disease and a more heterogeneous, less well-defined role in triple-negative breast cancer. In this narrative review, we integrate current evidence to examine the role of RAD18 in breast cancer radioresistance and to evaluate how RAD18-mediated DNA damage tolerance may be functionally embedded within broader PAM-driven survival programs. While existing data support a biologically plausible convergence between DNA damage tolerance mechanisms and oncogenic survival signaling, direct mechanistic evidence linking RAD18 to PAM pathway activity in breast cancer remains limited. We therefore propose a subtype-informed conceptual framework in which RAD18-dependent stress tolerance operates within a permissive survival signaling context. Such a framework may refine the interpretation of radioresistance and inform the development of predictive biomarkers as well as rational radiosensitization strategies.