RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Cancer Biology
• Genetics

Background:

• PARP inhibitors (PARPi) show promise in BRCA-deficient breast cancers, but resistance develops.
• The efficacy of PARPi in triple-negative breast cancers (TNBC) is unknown.
• Cancer stem cells (CSCs) in TNBC are linked to treatment resistance, metastasis, and recurrence.

Purpose of the Study:

• To determine the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and wild-type TNBC.
• To investigate the role of RAD51 in mediating CSC resistance to PARPi.

Main Methods:

• Assessed PARPi sensitivity of breast CSCs in BRCA1-mutant and wild-type TNBC cell lines and xenografts.
• Investigated RAD51's role in CSC resistance to PARPi using in vitro and in vivo models.
• Utilized shRNA to downregulate RAD51 and assess its impact on CSC sensitivity and tumor growth.

Main Results:

• CSCs in BRCA1-mutant TNBC exhibited resistance to PARPi, with elevated RAD51 levels and activity.
• Downregulating RAD51 sensitized BRCA1-mutant CSCs to PARPi and reduced tumor growth.
• BRCA1-wild-type cells showed relative resistance to PARPi alone, but RAD51 reduction sensitized both CSCs and bulk cells.

Conclusions:

• CSCs in both BRCA1-mutant and wild-type TNBC demonstrate relative resistance to PARP inhibition.
• RAD51 mediates this CSC resistance to PARPi.
• Targeting RAD51 may enhance the therapeutic effectiveness of PARPi in TNBC.