Abstract A33: Expression of BRCA2 and Mir-21 in sporadic and BRCA2 mutated breast cancer in Iceland

Abstract

Abstract The BRCA2 protein plays an important role in the repair of double-stranded DNA breaks (DSBs) by homologous recombination. An inherited founder mutation in the BRCA2 gene accounts for 6-7 % of all breast cancers in Iceland. Breast cancer in BRCA2 mutation carriers is associated with poor long-term prognosis. It has been reported that > 20% of sporadic breast cancers display a BRCA-like phenotype (BRCA‘ness), suggesting a defect in the DSB repair pathway. Little is known about the role of miRNAs in BRCA2 related breast cancer. Analysis of array CGH data from BRCA2 breast tumors shows that the mir-21 locus on chromosome 17 is amplified in > 70% of BRCA2 breast tumors. Mir-21 is a known oncomir with known target genes involved in tumor suppression, amongst others. High expression of mir-21 has been associated with poor-prognosis in other breast cancer populations. The aim of the study is to investigate the level and variation of BRCA2 and mir-21 expression in breast tumors from BRCA2 mutation carriers and breast tumors from non-carriers. Furthermore we want to see if there is association between BRCA2 and mir-21 expression. Expression analysis was performed by qPCR on RNA extracted from fresh frozen tumor tissue from BRCA2 mutation carriers and sporadic breast tumors. Expression of mir-21 was analyzed using specific mir-21 Taqman probes, with RNU48 as an endogenous control. Expression of BRCA2 was analyzed using gene specific primers detected by SYBR® Green, with HPRT1 as an endogenous control. To examine clinical relevance, we examine clinicopathological parameters including grade, nodal status, time to relapse and overall survival. Results from the BRCA2 expression analysis reveal significantly lower expression in the BRCA2 group compared to the sporadic group (as expected). However, BRCA2 expression shows a large degree of variation within both groups, with a greater than 20 fold difference between the highest and the lowest expression values. Results from the mir-21 expression analysis reveal a tendency towards a higher mir-21 expression in the BRCA2 group, although not statistically significant. When analyzing the BRCA2 and mir-21 expression data together we see a definite trend towards a negative correlation, where lower BRCA2 expression tends to associate with higher mir-21 expression. Our preliminary data thus show variability in BRCA2 expression, both among BRCA2 mutation carriers and non-carriers, as well as strong indications of negative association between BRCA2 and mir-21 expression. This information could be useful with respect to therapeutic strategies, e.g. making use of PARP inhibitors. Inhibitors targeting mir-21 have been shown to reduce tumor growth in animal models of multiple myelomas. The BRCA2 group shows high expression of mir-21 raising the possibility of using mir-21 inhibitors in patients with BRCA2 deficiency. Our results also indicate that mir-21 has an important role in BRCA2 carrier tumors as well as in sporadic cases. Note: This abstract was not presented at the conference. Citation Format: Sigridur Thora Reyisdottir, Sigridur Thora Reynisdottir, Olafur Andri Stefansson, Sigridur Klara Bödvarsdottir, Arnar Palsson, Jorunn Erla Eyfjörd. Expression of BRCA2 and Mir-21 in sporadic and BRCA2 mutated breast cancer in Iceland. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A33.