Werner Syndrome Protein Expression in Breast Cancer

Savva, Constantinos; Sadiq, Maaz; Sheikh, Omar; Karim, Syed; Trivedi, Sachin; Green, Andrew R.; Rakha, Emad A.; Madhusudan, Srinivasan; Arora, Arvind

Abstract

Introduction
Werner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS), which is characterized by premature aging and cancer predisposition. Malignancies that are commonly linked to WS are thyroid carcinoma, melanoma, breast cancer, meningioma, and soft tissue and bone sarcomas. Currently, the clinicopathologic significance of WRN in breast cancer is largely unknown.

Patients and Methods
We investigated the clinicopathologic and prognostic significance of WRN protein expression in a cohort of clinically annotated series of sporadic (n = 1650) and BRCA-mutated (n = 75) invasive breast cancers. We correlated WRN protein expression to clinicopathologic characteristics, DNA repair protein expression, and survival outcomes.

Results
There is strong evidence of association between low nuclear and cytoplasmic WRN co-expression and low levels of KU70/KU80, DNA-PK, DNA Pol-B, CKD18, cytoplasmic RECQL4, and nuclear BLM protein expression (adjusted P-values < .05). Tumors with low nuclear or cytoplasmic WRN expression have worse overall breast cancer-specific survival (BCSS) (adjusted P-values < .05). In topoisomerase I overexpressed tumors, low WRN nuclear expression was associated with poor BCSS (P-value < .05). In BRCA-mutated tumors, low WRN cytoplasmic expression conferred shortest BCSS (P < .05).

Conclusions
Low WRN protein expression is associated with poor BCSS in patients with breast cancer. This can be used to optimize the risk stratification for personalized treatment.

Citation

Savva, C., Sadiq, M., Sheikh, O., Karim, S., Trivedi, S., Green, A. R., …Arora, A. (2021). Werner Syndrome Protein Expression in Breast Cancer. Clinical Breast Cancer, 21(1), 57-73.E7. https://doi.org/10.1016/j.clbc.2020.07.013

• Journal Article Type: Article
• Acceptance Date: Jul 16, 2020
• Online Publication Date: Jul 25, 2020
• Publication Date: 2021-02
• Deposit Date: Jun 22, 2021
• Publicly Available Date: Jul 26, 2021
• Journal: Clinical Breast Cancer
• Print ISSN: 1526-8209
• Electronic ISSN: 1938-0666
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 1
• Pages: 57-73.E7
• DOI: https://doi.org/10.1016/j.clbc.2020.07.013
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/5718978
• Publisher URL: https://www.clinical-breast-cancer.com/article/S1526-8209(20)30179-8/fulltext
• Additional Information: This article is maintained by: Elsevier; Article Title: Werner Syndrome Protein Expression in Breast Cancer; Journal Title: Clinical Breast Cancer; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.clbc.2020.07.013; Content Type: article; Copyright: © 2020 Elsevier Inc. All rights reserved.