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

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.

SUBMITTER: Algethami M

PROVIDER: S-EPMC10063624 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Algethami Mashael M Toss Michael S MS Woodcock Corinne L CL Jaipal Chandar C Brownlie Juliette J Shoqafi Ahmed A Alblihy Adel A Mesquita Katia A KA Green Andrew R AR Mongan Nigel P NP Jeyapalan Jennie N JN Rakha Emad A EA Madhusudan Srinivasan S

NPJ breast cancer 20230330 1

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 ...[more]

PMID: 36997566

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Project description:Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial. Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers. Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293-1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250-2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602-4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762-4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114-1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010-1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022-2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China. Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis.

Dataset Information

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

Publications

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

Similar Datasets

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