Replication Protein A (RPA), a heterotrimeric complex consisting of RPA1, 2, and 3 subunits, is a
single-stranded DNA (ssDNA)-
binding protein that is critically involved in replication, checkpoint regulation and DNA repair. Here we have evaluated RPA in 776 pure
ductal carcinomas in situ (
DCIS), 239
DCIS that co-exist with invasive
breast cancer (IBC), 50 normal breast tissue and 4221 IBC. Transcriptomic [METABRIC cohort (n = 1980)] and genomic [TCGA cohort (n = 1090)] evaluations were completed. Preclinically, RPA deficient cells were tested for
cisplatin sensitivity and
Olaparib induced synthetic lethality. Low RPA linked to aggressive
DCIS, aggressive IBC, and shorter survival outcomes. At the transcriptomic level, low RPA tumours overexpress pseudogene/
lncRNA as well as genes involved in chemical
carcinogenesis, and
drug metabolism. Low RPA remains linked with poor outcome. RPA deficient cells are sensitive to
cisplatin and
Olaparib induced synthetic lethality. We conclude that RPA directed precision oncology strategy is feasible in breast
cancers.