title: Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers.
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.
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK, Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton campus, Nottingham NG11 8NS, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Doherty
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MA 21224-6825, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Moseley
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hameed
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK and.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK and.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology, Medical School Sheffield Cancer Research Centre, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Patterson
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton campus, Nottingham NG11 8NS, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Stephen Y T
authors.initials: SY
authors.lastname: Chan
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MA 21224-6825, USA.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MA 21224-6825, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Academic Unit of Molecular Oncology, Department of Oncology, Medical School Sheffield Cancer Research Centre, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Bryant
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK, Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK, srinivasan.madhusudan@nottingham.ac.uk.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051135:Rad51 Recombinase / Q000096:biosynthesis / Q000235:genetics; D053484:RecQ Helicases / Q000096:biosynthesis* / Q000235:genetics; D046888:Tissue Array Analysis
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C506732:RECQL5 protein, human; D012333:RNA, Messenger; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D053484:RecQ Helicases; D004250:DNA Topoisomerases, Type II