IFI16 Enhances Chemosensitivity of Breast Cancer Cells by Inhibiting DNA Damage Response

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Chemotherapy efficacy relies on cancer cells' DNA damage response (DDR).
• Interferon gamma-inducible protein 16 (IFI16) role in DDR and chemosensitivity is unexplored.
• Understanding DDR modulators can improve cancer treatment.

Purpose of the Study:

• Investigate IFI16's function in breast cancer cell DDR.
• Determine IFI16's impact on chemosensitivity to DNA-damaging agents.
• Evaluate IFI16 as a predictive biomarker for chemotherapy response.

Main Methods:

• Depletion of IFI16 in MDA-MB-231 breast cancer cells.
• Treatment with doxorubicin and 5-fluorouracil.
• Assessment of cell viability, apoptosis, and DNA damage markers (γH2AX, 53BP1).
• Analysis of MRE11-RAD50-NBS1 complex and ATM interaction.
• Xenograft tumor studies and analysis of patient datasets.

Main Results:

• IFI16 depletion increased resistance to doxorubicin and 5-fluorouracil.
• IFI16 interacts with MRE11-RAD50-NBS1, disrupting NBS1-ATM interaction and ATM activation.
• IFI16 knockout tumors showed reduced doxorubicin response and DNA damage signaling.
• High IFI16 expression correlated with better pathological complete response in patients.

Conclusions:

• IFI16 is crucial for DNA damage response and chemosensitivity in breast cancer.
• IFI16 acts by modulating ATM activation via the MRE11-RAD50-NBS1 complex.
• IFI16 shows potential as a predictive biomarker and therapeutic target for improving chemotherapy efficacy.