RNF8 over-expression promotes genomic instability in aggressive breast cancer

TNBC is associated with extensive genomic instability where double-strand breaks (DSB) are the most consequential DNA lesions. Knockdown of the RNF8 inhibits focus formation at DSB sites, suggesting that RNF8 is an essential regulator of the DNA repair system. We are investigating whether RNF8 acts as a regulator of BRCA1 and 53BP1 proteins in human breast cancers. We analyzed 57 FFPE human breast cancers taken from a population of Mexican women enriched for basal-like cancer if altered RNF8, 53BP1, CB1, and Ki67mRNA expression occurs compared to median expression as a reference value. RNF8 transcript levels varied among human breast cancers. The combined effect RNF8 high/53BP1 low was associated with high expression of Ki67 (p=0.028). Conversely, RNF8 low expression was associated with low expression of Ki67(p = 0.017), and CB1 low (p = 0.035) independent of the 53BP1 expression. Differential expression of RNF8 and 53BP1 in a series of human breast cancers and the association between RNF8/53BP1 levels and the tumor phenotype was demonstrated. Our findings suggest that some breast tumors have an altered DNA repair pathway resulting in activation of RNF8 and de-regulation of 53BP1, which may contribute to the genomic instability in more aggressive tumors.