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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3306-6) contains supplementary material, which is available to authorized users.

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…The BRCA1 and BRCA2 are known for their role in transcription, double strand break repair, recombination, tumor suppressor and maintenance of genomic stability [31]. In past decade, findings support that breast cancer due to germ line mutation in BRCA1 and BRCA2 genes display distinct morphology, immunophenotype and molecular characteristics from age-matched sporadic breast cancer cases [1,3,4,6,25,26,27].…”

“…The breast cancer is commonly classified according to hormone receptor (in particular estrogen and progesterone receptors) and epidermal growth factor receptor ErbB2/HER2 presence [1,6,26,27]. According to this classification, breast carcinoma is named as hormone receptor positive; hormone receptor negative with HER2 over-expression; triple negative breast cancer which does not express any of the three receptors.…”

“…But, discernible bottleneck is the less response towards genomic insults due to the acquired survival strategy by breast carcinoma [1,3,25]. Specifically, triple-negative breast cancers (TNBC) referred as hormone receptor negative (hormone insensitive) and HER-2 negative display inactivation of BRCA1 and DNA repair defects [4,25,26,27]. Besides tumor grade, molecular subtypes are preferentially used in the research settings, where Luminal A is classified as ER-positive and/or PR-positive, HER2-negative with Low Ki67.…”

“…Another breast carcinoma molecular subtype is referred as Luminal B defined by ER-positive and/or PR-positive, HER2-positive (or HER2-negative with high Ki67) with prevalence around 10-20%. Another molecular subtype as Triple negative/basal-like is noted as ER-negative/PR-negative/HER2-negative with prevalence of around 15-20% [1,3,4,6,[25][26][27]. Besides another molecular subtype as HER2posses ER-negative/PR-negative/HER2-positive characteristics with prevalence of 5-15%.…”

“…Breast cancer phenotypes are broadly classified as inherited vs sporadic in nature. The genetic contributions to breast cancer are elucidated as presence of several autosomal dominant cancer syndromes mostly with highly penetrant germline mutations in BRCA1 and BRCA2 [4,6,26,27]. Breast cancers around 5-10% are classified as hereditary breast carcinoma and known gene players such as BRCA1, BRCA2, CHEK2, BRIP1, RAD51 and ATM linked with breast cancers with moderate penetrance [6,30].…”