Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB mediated inflammatory response in Triple Negative Breast Cancer

Sher, E.; Fujihara, K.; Tao, A.; Erenburg, D.; Sviderskiy, V.; Mir, H.; Karakousi, T. R.; Loomis, C.; Deng, J.; Wong, K.-K.; Possemato, R.

doi:10.1101/2025.09.18.677147

bioRxiv · 10.1101/2025.09.18.677147

Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB mediated inflammatory response in Triple Negative Breast Cancer

Sher, E.·Fujihara, K.·Tao, A.·Erenburg, D.·Sviderskiy, V.·Mir, H.·Karakousi, T. R.·Loomis, C.·Deng, J.·Wong, K.-K.·Possemato, R.

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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-{kappa}B. TNBC cells exhibit markedly higher levels of DNA damage and canonical NF-{kappa}B activation compared to luminal breast cancer cells. Notably, NF-{kappa}B 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-{kappa}B 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-{kappa}B-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.

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Sher, E., Fujihara, K., Tao, A., Erenburg, D., Sviderskiy, V., Mir, H., Karakousi, T. R., Loomis, C., Deng, J., Wong, K.-K., Possemato, R.. 2025-09-18. Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB mediated inflammatory response in Triple Negative Breast Cancer. https://doi.org/10.1101/2025.09.18.677147

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