Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

Arora, A, Abdel-Fatah, TMA, Agarwal, D, Doherty, R, Moseley, PM, Aleskandarany, MA, Green, AR, Ball, G ORCID: 0000-0001-5828-7129, Alshareeda, AT, Rakha, EA, Chan, SYT, Ellis, IO and Madhusudan, S, 2015. Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer. Molecular Cancer Therapeutics, 14 (4), pp. 1057-1065. ISSN 1535-7163

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Abstract

BLM has key roles in homologous recombination repair, telomere maintenance and DNA replication. Germ-line mutation in the BLM gene causes Bloom’s syndrome, a rare disorder characterised by premature aging and predisposition to multiple cancers including breast cancer. The clinicopathological significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n=1950) and validated in an external dataset of 2413 tumours. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1650 breast tumours. High BLM mRNA expression was highly significantly associated with high histological grade, larger tumour size, ER negative, PgR negative and triple negative phenotypes (ps<0.0001). High BLM mRNA expression was also linked to aggressive molecular phenotypes including PAM50.Her2 (p<0.0001), PAM50.Bas al (p<0.0001) and PAM50.LumB (p<0.0001) and Genufu subtype (ER+/Her2-/High proliferation) (p<0.0001). PAM50.LumA tumours and Genufu subtype (ER+/Her2-/low proliferation) were more likely to express low levels of BLM mRNA (ps<0.0001). Integrative molecular clusters (intClust) intClust.1 (p<0.0001), intClust.5 (p<0.0001), intClust.9 (p<0.0 001) and intClust.10 (p<0.0001) were also more likely in tumours with high BLM mRNA expression. High BLM mRNA expression was associated with poor breast cancer specific survival (BCSS) (ps<0.000001). At the protein level, altered sub-cellular localisation with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS ( p=0.03). This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer.

Item Type: Journal article
Publication Title: Molecular Cancer Therapeutics
Creators: Arora, A., Abdel-Fatah, T.M.A., Agarwal, D., Doherty, R., Moseley, P.M., Aleskandarany, M.A., Green, A.R., Ball, G., Alshareeda, A.T., Rakha, E.A., Chan, S.Y.T., Ellis, I.O. and Madhusudan, S.
Publisher: American Association for Cancer Research
Date: 2015
Volume: 14
Number: 4
ISSN: 1535-7163
Identifiers:
NumberType
10.1158/1535-7163.MCT-14-0939DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 09 Feb 2016 15:58
Last Modified: 09 Jun 2017 13:59
URI: http://irep.ntu.ac.uk/id/eprint/26918

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