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

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

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


Mohammed Aleskandarany

Daniela Caracappa

Christopher C. Nolan

R. Douglas Macmillan

Professor of Breast Cancer Pathology


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.


Aleskandarany, M., Caracappa, D., Nolan, C. C., Macmillan, R. D., Ellis, I. O., Rakha, E. A., & Green, A. R. (2015). DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Research and Treatment, 150(1), 81-90.

Journal Article Type Article
Acceptance Date Feb 9, 2015
Online Publication Date Feb 19, 2015
Publication Date 2015-02
Deposit Date Oct 17, 2018
Publicly Available Date Oct 17, 2018
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 150
Issue 1
Pages 81-90
Keywords DNA repair; DNA damage response; BRCA-mutated breast cancers
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