Replication-Poison Treatment in BRCA1-Deficient Breast Cancer Causes MRE11 Over-Resection That Induces...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• BRCA1 deficiency is prevalent in triple-negative breast cancer (TNBC), impacting DNA repair pathways.
• BRCA1 plays a critical role in homologous recombination repair and stalled replication fork protection.

Purpose of the Study:

• To investigate the sensitivity of BRCA1-deficient TNBC models to gemcitabine, a replication chain terminator.
• To elucidate the DNA damage response mechanisms in BRCA1-deficient cells treated with gemcitabine.

Main Methods:

• Utilized BRCA1-deficient and proficient TNBC cell models.
• Treated cells with gemcitabine and assessed sensitivity, ssDNA accumulation, and DNA repair foci (RPA, RAD51).
• Investigated the role of MRE11 and olaparib (PARP1/2 inhibitor) in gemcitabine-induced DNA damage.

Main Results:

• BRCA1-deficient TNBC cells exhibited significant sensitivity to gemcitabine compared to proficient cells.
• Gemcitabine treatment led to massive single-stranded DNA (ssDNA) accumulation and lack of RPA/RAD51 foci in BRCA1-deficient cells.
• MRE11 inhibition reduced gemcitabine-induced ssDNA accumulation; olaparib did not cause MRE11-dependent over-resection.
• Cells with massive ssDNA accumulation underwent mitotic catastrophe, forming micronuclei and DNA bridges.

Conclusions:

• Gemcitabine treatment in BRCA1-deficient TNBC exposes unprotected nascent DNA, leading to MRE11-dependent over-resection and ssDNA accumulation.
• This hypersensitivity suggests gemcitabine could be a valuable therapeutic addition for BRCA1-deficient TNBC.
• The study highlights a novel mechanism of gemcitabine-induced cell death in BRCA1-deficient cancers.