Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB-mediated inflammatory response...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Triple-negative breast cancer (TNBC) has a poor prognosis.
• DNA replication is a critical process in cancer cell proliferation.
• Understanding TNBC-specific vulnerabilities is crucial for developing new therapies.

Purpose of the Study:

• To investigate the effects of suppressing DNA polymerase epsilon (POLE) in TNBC.
• To elucidate the molecular mechanisms linking POLE suppression to TNBC-specific responses.
• To evaluate the therapeutic potential of POLE inhibition in TNBC.

Main Methods:

• Genetic and pharmacological inhibition of POLE in TNBC cell lines and a murine TNBC model.
• Analysis of gene expression signatures, focusing on NF-κB pathway activation.
• Assessment of DNA damage levels and immune cell infiltration.

Main Results:

• POLE suppression in TNBC induces a unique gene expression signature enriched in NF-κB-dependent inflammatory cytokines.
• TNBC cells show higher DNA damage and NF-κB activation compared to luminal breast cancer cells.
• ATM, STING, and RIG-I signaling pathways contribute to NF-κB activation upon POLE suppression.
• In vivo, POLE suppression leads to tumor eradication and increased immune cell infiltration in a TNBC model.

Conclusions:

• Replication stress induced by POLE inhibition triggers robust NF-κB-mediated inflammation and immune remodeling in TNBC.
• POLE suppression can independently lead to tumor eradication in TNBC.
• Targeting POLE represents a promising therapeutic strategy for TNBC.