Abstract
BackgroundThe BRCA1 gene plays a key role in triple negative breast cancers (TNBCs), in which its expression can be lost by multiple mechanisms: germinal mutation followed by deletion of the second allele; negative regulation by promoter methylation; or miRNA-mediated silencing. This study aimed to establish a correlation among the BRCA1-related molecular parameters, tumor characteristics and clinical follow-up of patients to find new prognostic factors.MethodsBRCA1 protein and mRNA expression was quantified in situ in the TNBCs of 69 patients. BRCA1 promoter methylation status was checked, as well as cytokeratin 5/6 expression. Maintenance of expressed BRCA1 protein interaction with BARD1 was quantified, as a marker of BRCA1 functionality, and the tumor expression profiles of 27 microRNAs were determined.ResultsmiR-548c-5p was emphasized as a new independent prognostic factor in TNBC. A combination of the tumoral expression of miR-548c and three other known prognostic parameters (tumor size, lymph node invasion and CK 5/6 expression status) allowed for relapse prediction by logistic regression with an area under the curve (AUC) = 0.96.BRCA1 mRNA and protein in situ expression, as well as the amount of BRCA1 ligated to BARD1 in the tumor, lacked any associations with patient outcomes, likely due to high intratumoral heterogeneity, and thus could not be used for clinical purposes.ConclusionsIn situ BRCA1-related expression parameters could be used for clinical purposes at the time of diagnosis. In contrast, miR-548c-5p showed a promising potential as a prognostic factor in TNBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1740-9) contains supplementary material, which is available to authorized users.
Highlights
The Breast cancer susceptibility gene 1 (BRCA1) gene plays a key role in triple negative breast cancers (TNBCs), in which its expression can be lost by multiple mechanisms: germinal mutation followed by deletion of the second allele; negative regulation by promoter methylation; or miRNA-mediated silencing
Quantification of in situ BRCA1 messenger RNAs (mRNAs) and protein expression To assess the BRCA1 expression status inside the tumors, the amount of BRCA1 protein was first measured by proximity ligation assays (PLAs) in fixed TNBC tissues
The most striking observation was that the staining for both mRNA and protein is heterogeneous across the tumor: some areas strongly expressed BRCA1 and others only faintly, as illustrated in the two magnified subzones
Summary
The BRCA1 gene plays a key role in triple negative breast cancers (TNBCs), in which its expression can be lost by multiple mechanisms: germinal mutation followed by deletion of the second allele; negative regulation by promoter methylation; or miRNA-mediated silencing. BRCA1 is involved in large protein complexes and its BRCA1 seems to be associated with the triple negative breast cancer (TNBC) subtype because the histological features and clinical outcomes of TNBC sporadic tumors can be very similar to those found in the tumors of BRCA1 germline mutated patients. The traits that some sporadic cancers share with those occurring in BRCA1 mutation carriers were described and called ‘BRCAness’ by Turner et al [1]. These cancers present a high rate of chromosomal alterations reflecting the absence of the BRCA1 DNA repair function.
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