Heterozygous BRCA1 SNPs in the DNA Binding Domain Enhance Sensitivity to PARP Inhibition in Breast Cancer Cells

Poly(ADP-ribose) polymerase (PARP) inhibitors show efficacy in breast cancer patients with BRCA1/2 mutations. However, certain BRCA1 single nucleotide polymorphisms (SNPs) may alter protein function without complete loss of activity. This study investigates whether specific BRCA1 SNPs within the DNA binding domain affect cellular sensitivity to PARP inhibition. We used breast cancer cell lines with heterozygous BRCA1 SNPs (CAMA-1: rs799917, rs16941, rs16942, rs1799966) or wild-type BRCA1 (T47D). Cell viability was assessed following olaparib treatment using MTT assay. Transcriptome sequencing and functional enrichment analyses were performed. CAMA-1 cells exhibited significantly enhanced olaparib sensitivity compared to T47D cells, with viability reduced to 45% versus 75% at 50 μM after 72 hours (p<0.001). Transcriptome analysis revealed 6,978 differentially expressed genes, with enrichment in DNA binding, transcriptional regulation, and cellular degradation pathways, suggesting conditional haploinsufficiency under PARP inhibition stress. Heterozygous BRCA1 SNPs in the DNA binding domain confer increased PARP inhibitor sensitivity without pathogenic mutations. This suggests potential expansion of PARP inhibitor therapy to patients with specific BRCA1 polymorphisms, representing a novel biomarker for personalized breast cancer treatment.