Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin...

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• BRCA1 is crucial for DNA repair, particularly homologous recombination (HR).
• Emerging evidence suggests BRCA1 also influences base excision repair (BER).
• Targeting BRCA1-deficient cells, especially those with impaired BER, presents a potential therapeutic avenue in breast cancer.

Purpose of the Study:

• To investigate the relationship between BRCA1, XRCC1, and pol β expression in breast cancer.
• To evaluate the prognostic significance of XRCC1 and pol β in BRCA1-negative tumors.
• To explore the therapeutic potential of targeting BRCA1-BER deficient cells using ATM and DNA-PKcs inhibitors.

Main Methods:

• Analysis of BRCA1, XRCC1, and pol β protein and mRNA expression in human breast cancer cohorts.
• Artificial neural network analysis to identify BRCA1-DNA repair gene interactions.
• Pre-clinical evaluation of synthetic lethality in BRCA1-proficient and deficient cell lines using specific inhibitors and cisplatin.

Main Results:

• BRCA1 negativity strongly correlated with low XRCC1 and pol β expression at both mRNA and protein levels.
• In BRCA1-negative tumors, low XRCC1 or pol β expression was associated with significantly poorer patient survival.
• Pre-clinically, BRCA1-deficient cells demonstrated sensitivity to ATM and DNA-PKcs inhibitors, alone or with cisplatin, leading to synthetic lethality.

Conclusions:

• XRCC1 and pol β expression levels may serve as prognostic markers in BRCA1-negative breast cancer.
• BRCA1-BER deficient cells are vulnerable to targeted therapy with ATM or DNA-PKcs inhibitors.
• This suggests a personalized therapeutic strategy for breast cancer patients with specific DNA repair deficiencies.