RECQL4 helicase has oncogenic potential in sporadic breast cancers

Media type: E-Article
Title: RECQL4 helicase has oncogenic potential in sporadic breast cancers
Contributor: Arora, Arvind; Agarwal, Devika; Abdel‐Fatah, Tarek MA; Lu, Huiming; Croteau, Deborah L; Moseley, Paul; Aleskandarany, Mohammed A; Green, Andrew R; Ball, Graham; Rakha, Emad A; Chan, Stephen YT; Ellis, Ian O; Wang, Lisa L; Zhao, Yongliang; Balajee, Adayabalam S; Bohr, Vilhelm A; Madhusudan, Srinivasan
imprint: Wiley, 2016
Published in: The Journal of Pathology
Language: English
DOI: 10.1002/path.4681
ISSN: 0022-3417; 1096-9896
Keywords: Pathology and Forensic Medicine
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">RECQL4</jats:styled-content> helicase is a molecular motor that unwinds <jats:styled-content style="fixed-case">DNA</jats:styled-content>, a process essential during <jats:styled-content style="fixed-case">DNA</jats:styled-content> replication and <jats:styled-content style="fixed-case">DNA</jats:styled-content> repair. Germ‐line mutations in <jats:italic><jats:styled-content style="fixed-case">RECQL4</jats:styled-content></jats:italic> cause type <jats:styled-content style="fixed-case">II</jats:styled-content> Rothmund–Thomson syndrome (<jats:styled-content style="fixed-case">RTS</jats:styled-content>), characterized by a premature ageing phenotype and cancer predisposition. <jats:italic><jats:styled-content style="fixed-case">RECQL4</jats:styled-content></jats:italic> is widely considered to be a tumour suppressor, although its role in human breast cancer is largely unknown. As the <jats:italic><jats:styled-content style="fixed-case">RECQL4</jats:styled-content></jats:italic> 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 (<jats:italic>n =</jats:italic> 1977), <jats:styled-content style="fixed-case">mRNA</jats:styled-content> expression (<jats:italic>n =</jats:italic> 1977) and protein level (<jats:italic>n =</jats:italic> 1902). Breast cancer incidence was also explored in 58 patients with type <jats:styled-content style="fixed-case">II RTS</jats:styled-content>. <jats:styled-content style="fixed-case">DNA</jats:styled-content> replication dynamics and chemosensitivity was evaluated in <jats:styled-content style="fixed-case">RECQL4</jats:styled-content>‐depleted breast cancer cells <jats:italic>in vitro</jats:italic>. Amplification or gain in gene copy number (30.6%), high‐level <jats:styled-content style="fixed-case">mRNA</jats:styled-content> expression (51%) and high levels of protein (23%) significantly associated with aggressive tumour behaviour, including lymph node positivity, larger tumour size, <jats:styled-content style="fixed-case">HER2</jats:styled-content> overexpression, <jats:styled-content style="fixed-case">ER</jats:styled-content>‐negativity, triple‐negative phenotypes and poor survival. <jats:styled-content style="fixed-case">RECQL4</jats:styled-content> depletion impaired the <jats:styled-content style="fixed-case">DNA</jats:styled-content> 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 <jats:styled-content style="fixed-case">RECQL4</jats:styled-content> is tumour promoting in established breast cancers. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</jats:p>

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