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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2015

Open Access 01-02-2015 | Preclinical study

DNA damage response markers are differentially expressed in BRCA-mutated breast cancers

Authors: Mohammed Aleskandarany, Daniela Caracappa, Christopher C. Nolan, R. Douglas Macmillan, Ian O. Ellis, Emad A. Rakha, Andrew R. Green

Published in: Breast Cancer Research and Treatment | Issue 1/2015

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Abstract

Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC.
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Metadata
Title
DNA damage response markers are differentially expressed in BRCA-mutated breast cancers
Authors
Mohammed Aleskandarany
Daniela Caracappa
Christopher C. Nolan
R. Douglas Macmillan
Ian O. Ellis
Emad A. Rakha
Andrew R. Green
Publication date
01-02-2015
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2015
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-015-3306-6

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