{"doi":"10.1101/2025.09.18.677147","title":"Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB-mediated inflammatory response in Triple Negative Breast Cancer","abstract":". 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-κB activation following POLE suppression. In vivo, POLE suppression in a murine TNBC model leads 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":575226,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1043931,"name":"Kenji M. Fujihara","orcid":"0000-0002-8387-4912","position":1,"is_corresponding":false},{"id":882401,"name":"Anthony Tao","orcid":"0000-0003-0978-2769","position":2,"is_corresponding":false},{"id":1483540,"name":"Diana Erenburg","orcid":null,"position":3,"is_corresponding":false},{"id":323544,"name":"Vladislav O. Sviderskiy","orcid":"0000-0002-9692-5328","position":4,"is_corresponding":false},{"id":323551,"name":"Hannan Mir","orcid":"0000-0002-6989-0713","position":5,"is_corresponding":false},{"id":323546,"name":"Triantafyllia Karakousi","orcid":"0000-0002-1950-7341","position":6,"is_corresponding":false},{"id":75654,"name":"Cynthia A. Loomis","orcid":"0000-0001-8668-1270","position":7,"is_corresponding":false},{"id":58548,"name":"Jiehui Deng","orcid":"0000-0001-7986-8643","position":8,"is_corresponding":false},{"id":20939,"name":"Kwok‐Kin Wong","orcid":"0000-0001-6323-235X","position":9,"is_corresponding":false},{"id":273822,"name":"Richard Possemato","orcid":"0000-0002-2401-0030","position":10,"is_corresponding":false},{"id":323545,"name":"Elizabeth Gorodetsky","orcid":"0000-0003-3977-1702","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":"41000653","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}