title: RECQL4 helicase has oncogenic potential in sporadic breast cancers.
abstract: RECQL4 helicase is a molecular motor that unwinds DNA, a process essential during DNA replication and DNA repair. Germ-line mutations in RECQL4 cause type II Rothmund-Thomson syndrome (RTS), characterized by a premature ageing phenotype and cancer predisposition. RECQL4 is widely considered to be a tumour suppressor, although its role in human breast cancer is largely unknown. As the RECQL4 gene is localized to chromosome 8q24, a site frequently amplified in sporadic breast cancers, we hypothesized that it may play an oncogenic role in breast tumourigenesis. To address this, we analysed large cohorts for gene copy number changes (n = 1977), mRNA expression (n = 1977) and protein level (n = 1902). Breast cancer incidence was also explored in 58 patients with type II RTS. DNA replication dynamics and chemosensitivity was evaluated in RECQL4-depleted breast cancer cells in vitro. Amplification or gain in gene copy number (30.6%), high-level mRNA expression (51%) and high levels of protein (23%) significantly associated with aggressive tumour behaviour, including lymph node positivity, larger tumour size, HER2 overexpression, ER-negativity, triple-negative phenotypes and poor survival. RECQL4 depletion impaired the DNA replication rate and increased chemosensitivity in cultured breast cancer cells. Thus, although recognized as a 'safe guardian of the genome', our data provide compelling evidence that RECQL4 is tumour promoting in established breast cancers. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK.|Department of Oncology, Nottingham University Hospitals, UK.
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Department of Oncology, Nottingham University Hospitals, UK.
authors.forename: Tarek Ma
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Ageing, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Ageing, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Department of Oncology, Nottingham University Hospitals, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Oncology, Nottingham University Hospitals, UK.
authors.forename: Stephen Yt
authors.initials: SY
authors.lastname: Chan
authors.affiliation: Department of Pathology, School of Medicine, University of Nottingham, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: REAC/TS, Oak Ridge Associated Universities, Oak Ridge Institute for Science and Education, TN, USA.
authors.forename: Adayabalam S
authors.initials: AS
authors.lastname: Balajee
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Ageing, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK.|Department of Oncology, Nottingham University Hospitals, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D005260:Female; D006801:Humans; D010641:Phenotype; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D053484:RecQ Helicases; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C506731:RECQL4 protein, human
keywords: RECQL4 helicase; breast cancer; oncogene; tumour suppressor