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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.

SUBMITTER: Arora A

PROVIDER: S-EPMC5576893 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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RECQL4 helicase has oncogenic potential in sporadic breast cancers.

Arora Arvind A Agarwal Devika D Abdel-Fatah Tarek Ma TM Lu Huiming H Croteau Deborah L DL Moseley Paul P Aleskandarany Mohammed A MA Green Andrew R AR Ball Graham G Rakha Emad A EA Chan Stephen Yt SY Ellis Ian O IO Wang Lisa L LL Zhao Yongliang Y Balajee Adayabalam S AS Bohr Vilhelm A VA Madhusudan Srinivasan S

The Journal of pathology 20160202 4

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 hypothesi ...[more]

PMID: 26690729

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Project description:BackgroundWhile a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use.MethodsmiRNA expression was assessed in 11 BRCA1 basal, 16 sporadic basal, 17 luminal grade 3 cancers via microarrays. The expression of Cyclin D1, FOXP1, FIH-1, pan-ERβ, NRP1 and CD99, predicted to be regulated by BRCA1 specific miRNAs by computer prediction algorithms, was assessed via immunohistochemistry in a cohort of 35 BRCA1 and 52 sporadic basal-like cancers. Assessment of cyclin D1, FOXP1, NRP1 and CD99 expression was repeated on a validation cohort of 82 BRCA1 and 65 sporadic basal-like breast cancers.ResultsUnsupervised clustering of basal cancers resulted in a "sporadic" cluster of 11 cancers, and a "BRCA1" cluster of 16 cancers, including a subgroup composed entirely of 10 BRCA1 cancers. Compared with sporadic basal cancers, BRCA1 cancers showed reduced positivity for proteins predicted to be regulated by miRNAs: FOXP1 (6/20[30 %] vs. 37/49[76 %], p < 0.001), cyclin D1 (8/22[36 %] vs. 30/46[65 %], p = 0.025), NRP1 (2/20[10 %] vs. 23/46[50 %], p = 0.002). This was confirmed in the validation cohort (all p < 0.001). Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.ConclusionSporadic and BRCA1 basal-like cancers have grade independent miRNA expression profiles. Furthermore miRNA driven differences in the expression of proteins in BRCA1 basal cancers may be detected via immunohistochemistry. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.

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RECQL4 helicase has oncogenic potential in sporadic breast cancers.

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RECQL4 helicase has oncogenic potential in sporadic breast cancers.

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