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Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5–7% of overall breast cancer. To define the characteristics of these tumors and also to identify tumors without BRCA mutation but with homologous recombination deficiency (HRD) is clinically relevant. To define characteristic features of HRD tumors and analyze the correlations between BRCA1/BRCA2 and BC subtypes, we analyzed 981 breast tumors from the TCGA database using the signature analyzer. The BRCA signature was strongly associated with the HRD score top 10% (score ≥ 57) population. This population showed a high level of mutations in DDR genes, including BRCA1/BRCA2. HRD tumors were associated with high expression levels of BARD1 and BRIP1. Besides, BRCA1/2 mutations were dominantly observed in basal and luminal subtypes, respectively. A comparison of HRD features in BC revealed that BRCA1 exerts a stronger influence inducing HRD features than BRCA2 does. It reveals genetic differences between BRCA1 and BRCA2 and provides a basis for the identification of HRD and other BRCA-associated tumors.

Triple negative breast cancer (TNBC) is characterized by an aggressive biological behavior in the absence of a specific target agent. Nicotinamide has recently been proven to be a novel therapeutic agent for skin tumors in an ONTRAC trial. We performed combinatory transcriptomic and in-depth proteomic analyses to characterize the network of molecular interactions in TNBC cells treated with nicotinamide. The multi-omic profiles revealed that nicotinamide drives significant functional alterations related to major cellular pathways, including the cell cycle, DNA replication, apoptosis and DNA damage repair. We further elaborated the global interaction networks of molecular events via nicotinamide-inducible expression changes at the mRNA and functional protein levels. This approach indicated that nicotinamide treatment rewires interaction networks toward dysfunction in DNA damage repair and away from a pro-growth state in TNBC. To our knowledge, the high-resolution network interactions identified in the present study provide the first evidence to comprehensively support the hypothesis of nicotinamide as a novel therapeutic agent in TNBC.