title: DNA damage response markers are differentially expressed in BRCA-mutated breast cancers.
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.
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK, Mohammed.Aleskandarany@nottingham.ac.uk.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aleskandarany
authors.forename: Daniela
authors.initials: D
authors.lastname: Caracappa
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nolan
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Macmillan
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic; D063868:Patient Outcome Assessment; D011379:Prognosis; D012189:Retrospective Studies; D047368:Tumor Burden
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor