Abstract
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.
Highlights
Triple negative breast cancer (TNBC) accounts for 10–20% of all breast cancers and is generally associated with a worse prognosis than that of non-TNBC as a result of its aggressive biological behavior and the lack of targeted therapeutic strategies
Cell cycle analysis and apoptosis assay revealed that nicotinamide triggered S or G1 phase arrest and apoptosis in all kinds of TNBC cells, respectively (Supplementary Fig. S2)
The APC/C (ANAPC)-CDH1 complex, another signaling axis related to the G2/M phase, primarily mediates the degradation of regulators of cytokinesis and centrosome replication and targets the A/B types of mitotic cyclins and FOXM1 for destruction[22] for the negative regulation of Aurora A (AURKA) and PLK123. These results demonstrated that the expression of these factors was significantly decreased following nicotinamide treatment, which caused the reactivation of the APC/C (ANAPC)-CDH1 complex and played another role in G2/M arrest through cyclin B1 (CCNB1) inactivation
Summary
Triple negative breast cancer (TNBC) accounts for 10–20% of all breast cancers and is generally associated with a worse prognosis than that of non-TNBC as a result of its aggressive biological behavior and the lack of targeted therapeutic strategies. Most previous studies have reflected single or a limited number of molecular events, which thereby limits the current understanding of the entire spectrum of complex molecular alterations and interaction networks accompanied by nicotinamide treatment in cancer cells. Interest in personalized cancer therapy has led to numerous advances in the field of cancer genomics, and next-generation sequencing represents one development that elaborates various types of genomic alterations. It remains unclear whether genomic events are eventually translated into proteomes, which are the final functional units within a cell. Previous studies have exhibited considerable discordance between genomic mutations and protein levels[6, 7]
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