Targeting DNA Polymerase Epsilon Induces Tumor Clearance and Activates an NF-κB–Mediated Inflammatory Response in Triple-Negative Breast Cancer

Abstract Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor 5-year prognosis. In this study, we have demonstrated that among genetic and pharmacologic perturbations targeting DNA replication, suppression of the DNA polymerase epsilon catalytic subunit (POLE) induced a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibited markedly higher levels of DNA damage and canonical NF-κB activation compared with luminal breast cancer cells. Notably, NF-κB activation in this context depended on the canonical component RELA but not on the noncanonical component RELB. Mechanistically, ataxia–telangiectasia mutated, stimulator of IFN genes, and retinoic acid–inducible gene I each contributed to NF-κB activation following POLE suppression. POLE suppression in an in vivo murine TNBC model led to cancer cell–intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-κB–mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC. Significance: DNA replication protein POLE can be selectively targeted in triple-negative breast cancer to activate signaling pathways that increase expression of inflammatory genes dependent on canonical NF-κB signaling and to eradicate tumors.