复制蛋白A(RPA)是一个由RPA1、2和3亚基组成的异三聚体复合物，是一个单链DNA(ssDNA)结合蛋白，在复制、检查点调节和DNA修复中起着关键作用。我们在776例原位导管癌(DCIS)、239例与浸润性乳腺癌(IBC)共存的DCIS、50例正常乳腺组织和4221例IBC中评估了RPA。完成了转录组[METABRIC队列(n=1980)]和基因组[TCGA队列(n=1090)]评估。预临床研究中，RPA缺陷细胞被用于对顺铂敏感性和奥拉帕尼诱导的合成致死性进行测试。低RPA与侵袭性DCIS、侵袭性IBC和更短的生存结果相关。在转录组水平上，低RPA肿瘤过度表达伪基因/lncRNA以及参与化学致癌和药物代谢的基因。低RPA仍与不良结果相关。RPA缺陷细胞对顺铂和奥拉帕尼诱导的合成致死性敏感。我们得出结论，RPA定向的精准肿瘤学策略在乳腺癌中是可行的。©2023年，作者。

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.© 2023. The Author(s).