Abstract B47: Potential role for RNF8 in breast cancer development

Abstract

Abstract Background: Women of Mexican descent have a higher mortality and higher proportion of triple negative or basal-like breast cancers with BRCA like features and a higher population burden of BRCA mutations. Basal-like breast cancer subtype is associated with an elevated Ki67 index and extensive genomic instability. This increase in the Ki67 index indicates cell proliferation and perhaps greater cell DNA damage. In another report it was shown that knockdown of ring finger 8 (RNF8), an E3 ubiquitin-protein ligase, by siRNA inhibited focus formation at double strand break sites suggesting that RNF8 is an important regulator of the DNA repair system. We hypothesized that loss of RNF8 would be associated with more aggressive tumors such as those having high Ki67 levels. We are investigating the hypothesis that RNF8 is a tumor suppressor gene and acts as a novel regulatory protein of BRCA1 expression in human breast cancers. Methods: We tested whether 37 formalin fixed paraffin embedded human breast cancers taken from a population of Mexican women enriched for basal-like cancers show altered RNF8 and Ki67 mRNA expression compared to median expression as reference value. Results: Copy number differences in tumors for Ki67 and RNF8 mRNA were observed. The average differences in copy number for Ki67 between low and high expressing tumors was 8.8 fold and for RNF8 the average copy number differences between high and low expressors were 5.5 fold. When we compared the relationship between RNF8 and Ki67 expression within individual tumors, RNF8 expression was positively associated with Ki67 gene expression (p=0.04). Tumors that were high RNF8 were significantly more likely to also be high for Ki67. We found a non-significant but similar direction between RNF8 and cyclin B1 (p=0.08) but no relationship between RFN8 and cyclin D1 gene expression (p=0.318). This suggests that RNF8 is overexpressed in the tumors that are undergoing high mitoses. Conclusion: This is the first report demonstrating differential expression of RNF8 in a series of human breast cancers and a positive association between Ki67 and RNF8 levels. This finding is counter to our hypothesis that RNF8 acts as a tumor suppressor and that we would observe loss of gene expression. Interestingly, a recent study found that among BRCA deficient backgrounds, the involvement of an alternative DNA repair pathway that is prone to more mistakes involving p53 binding protein (53BP1), which interacts with RNF8 in cells, modifies susceptibility of the BRCA1 deficient background to carcinogenesis. Our findings may suggest that among some breast tumors overexpression of this altered DNA repair pathway including activation of RNF8 made contribute to the genomic instability in more aggressive tumors. Additional studies to assess the relationship between 53BP1 and RNF8 in these tumors are ongoing. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B47.