Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers

Arora, Arvind; Abdel-Fatah, Tarek M.A.; Agarwal, Devika; Doherty, Rachel; Croteau, Deborah L.; Moseley, Paul M.; Hameed, Khalid; Green, Andrew; Aleskandarany, Mohammed A.; Patterson, Karl; Rakha, Emad A.; Ball, Graham; Chan, Stephen Y.T.; Ellis, Ian O.; Bohr, Vilhelm A.; Bryant, Helen E.; Madhusudan, Srinivasan

Abstract

RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series ( n = 1650) and ER− cohort ( n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade ( P = 0.007), HER2 overexpression ( P = 0.032), ER+/HER2−/high proliferation genefu subtype ( P < 0.0001), integrative molecular clusters (intClust 1and 9) ( P < 0.0001) and poor survival ( P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort ( P < 0.0001) but not in ER− cohort ( P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade ( P < 0.0001), higher mitotic index ( P = 0.008), dedifferentiation ( P = 0.025), pleomorphism ( P = 0.027) and poor survival ( P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort ( P = 0.010), but not in ER− cohort ( P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival ( P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer.

Citation

Arora, A., Abdel-Fatah, T. M., Agarwal, D., Doherty, R., Croteau, D. L., Moseley, P. M., Hameed, K., Green, A., Aleskandarany, M. A., Patterson, K., Rakha, E. A., Ball, G., Chan, S. Y., Ellis, I. O., Bohr, V. A., Bryant, H. E., & Madhusudan, S. (2016). Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers. Carcinogenesis, 37(1), 63-71. https://doi.org/10.1093/carcin/bgv163

• Journal Article Type: Article
• Acceptance Date: Oct 30, 2015
• Online Publication Date: Nov 19, 2015
• Publication Date: 2016-01
• Deposit Date: Oct 16, 2018
• Publicly Available Date: Oct 18, 2018
• Journal: Carcinogenesis
• Print ISSN: 0143-3334
• Electronic ISSN: 1460-2180
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 37
• Issue: 1
• Pages: 63-71
• DOI: https://doi.org/10.1093/carcin/bgv163
• Public URL: https://nottingham-repository.worktribe.com/output/1170122
• Publisher URL: https://academic.oup.com/carcin/article/37/1/63/2365822
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Carcinogenesis following peer review. The version of record Arvind Arora, Tarek M.A. Abdel-Fatah, Devika Agarwal, Rachel Doherty, Deborah L. Croteau, Paul M. Moseley, Khalid Hameed, Andrew Green, Mohammed A. Aleskandarany, Emad A. Rakha, Karl Patterson, Graham Ball, Stephen Y.T. Chan, Ian O. Ellis, Vilhelm A. Bohr, Helen E. Bryant, Srinivasan Madhusudan; Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers, Carcinogenesis, Volume 37, Issue 1, 1 January 2016, Pages 63–71 is available online at: https://academic.oup.com/carcin/article/37/1/63/2365822.
• Contract Date: Oct 18, 2018