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Unravelling the clinicopathological and functional significance of replication protein A (RPA) heterotrimeric complex in breast cancers

Algethami, Mashael; Toss, Michael S.; Woodcock, Corinne L.; Jaipal, Chandar; Brownlie, Juliette; Shoqafi, Ahmed; Alblihy, Adel; Mesquita, Katia A.; Green, Andrew R.; Mongan, Nigel P.; Jeyapalan, Jennie N.; Rakha, Emad A.; Madhusudan, Srinivasan

Unravelling the clinicopathological and functional significance of replication protein A (RPA) heterotrimeric complex in breast cancers Thumbnail


Authors

Mashael Algethami

Michael S. Toss

Corinne L. Woodcock

Chandar Jaipal

Juliette Brownlie

Ahmed Shoqafi

Adel Alblihy

Katia A. Mesquita

Andrew R. Green

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Associate Pro-Vice Chancellorglobal Engagement

Jennie N. Jeyapalan

Emad A. Rakha



Abstract

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.

Citation

Algethami, M., Toss, M. S., Woodcock, C. L., Jaipal, C., Brownlie, J., Shoqafi, A., …Madhusudan, S. (2023). Unravelling the clinicopathological and functional significance of replication protein A (RPA) heterotrimeric complex in breast cancers. npj Breast Cancer, 9, Article 18. https://doi.org/10.1038/s41523-023-00524-3

Journal Article Type Article
Acceptance Date Mar 14, 2023
Online Publication Date Mar 30, 2023
Publication Date 2023
Deposit Date Apr 9, 2023
Publicly Available Date Apr 20, 2023
Journal npj Breast Cancer
Electronic ISSN 2374-4677
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 9
Article Number 18
DOI https://doi.org/10.1038/s41523-023-00524-3
Keywords Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Oncology
Public URL https://nottingham-repository.worktribe.com/output/19010351
Publisher URL https://www.nature.com/articles/s41523-023-00524-3

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