A significant percentage of BRCA1-associated breast cancers do not display a clear second hit (loss of heterozygosity, methylation, inactivating mutation) in a large part of the tumor cells. In patients with germline defects in BRCA1, microRNAs could potentially inhibit the remaining functional allele, thereby contributing to oncogenesis in a way similar to more conventional second hits. We hypothesize that overexpression of oncogenic microRNAs may play a role in downregulating the expression of the retained wild type BRCA1 allele, at least on a subclonal level.
Genome-wide microRNA expression profiling investigated the expression microRNAs in 51 BRCA1-associated breast cancers for which BRCA1 was thoroughly investigated at the (epi-)genetic level. We evaluated the association with molecular subtype and histopathological features, and with the presence of a residual functional BRCA1 allele using differential expression analysis. BRCA1 protein expression in these tumors was studied using immunohistochemistry.
We identified fourteen microRNAs upregulated in tumors retaining the BRCA1 wild type allele in > 50% of tumor cells. Differential expression analysis based on histopathological features of breast tumors was highly similar to publically available data from two prior independent studies. Intratumoral heterogeneity for BRCA1 protein expression was seen in several tumors, but did not always correlate to the observed amount of retained BRCA1 wild type allele.
Our study revealed candidate microRNAs that are potentially active in BRCA1-associated breast tumorigenesis. miRNAs upregulated in tumors with a retained functional BRCA1 allele, lacking BRCA1 protein expression might be involved in BRCA1 regulation. This regulation can occur in a direct or indirect manner and should be further functionally validated. microRNAs involved in BRCA1 regulation have the potential to sensitize tumors to PARP inhibitor or platinum-based therapies.
Ghent University.
‘Flanders Innovation and Entrepreneurship’ in the form of a doctoral basic strategic research grant [IWT/SB/131739] and the Ghent University Special Research Fund (BOF15/GOA/011).
All authors have declared no conflicts of interest.