Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of 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 five-year prognosis¹. Here, we demonstrate that among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) in TNBC, induces a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibit markedly higher levels of DNA damage and canonical NF-κB activation compared to luminal breast cancer cells. Notably, NF-κB activation in this context depends on the canonical component RELA, but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contribute to NF-κ

SUBMITTER: Sher EF 

PROVIDER: S-EPMC12458326 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature