FANCD2 in relation to BRCA2 mutated breast cancer

Breast cancer (BC) is the most common cancer among women in the world. Around 5-10% of BC is considered hereditary and caused by mutations in the BRCA1 and BRCA2 genes. BRCA1 and BRCA2 proteins have been shown to be involved in a multitude of pivotal cellular processes and are required for maintenance of chromosomal stability including DNA homologous recombination (HR) repair and DNA replication support. It has been shown that BRCA2 has an important role in maintaining the stability of chromosomal ends (Bodvarsdottir et al., 2012). It has also been demonstrated that when DNA HR repair is inactive because of BRCA1 or BRCA2 deficiency, more error prone DNA repair pathways controlled by PARP-1 and FANCD2, take over (Kais et al., 2016). Tissue staining for the active unit of telomerase (hTERT) and FANCD2 was performed on 470 BC samples on tissue microarrays (TMAs). It was evaluated whether overexpression of these proteins in the cell nuclei were associated with clinicopathological parameters or BC specific survival emphasizing BRCA2 mutation carriers. Another aim was to look for improved therapy options against olaparib PARP inhibition treatment tolerance with alisertib Aurora-A inhibition that could work against FANCD2 activation in cells lacking BRCA2 expression. Statistical significance was found for high FANCD2 nuclear expression and low age at diagnosis, larger tumor sizes, tumor grade and increased Ki-67 expression. The only statistical significance with high hTERT nuclear expression was found with lower tumor grades among BRCA2 mutation carriers. Neither hTERT nor FANCD2 nuclear staining were found to be associated with BC specific survival. BRCA2 and FANCD2 were knocked down by siRNA separately in the cell lines. When BRCA2 was knocked down an increase in FANCD2 expression was seen in the BRCA2 heterozygous breast cell line A176 but not in the control breast cell line MCF10A. There were no sufficient conclusions from the cell viability assay to evaluate the effect of FANCD2, Aurora-A and BRCA2 expression on response to medication. However, the results indicate that when A176 loses BRCA2 expression FANCD2 expression increases and leads to olaparib drug resistance.Göngum saman styrktarsjóður