23P - Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Breast Cancer
Presenter Han Suk Ryu
Authors H.S. Ryu1, D. Han2, K. Kim3
  • 1Pathology, Seoul National University Hospital, 03080 - Seoul/KR
  • 2Proteomic Core Facility, Seoul National University Hospital, 03080 - Seoul/KR
  • 3Bioinformatics, Seoul National University Hospital, 03080 - Seoul/KR

Abstract

Body

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. A systemic chemotherapeutic regimen is the only reliable treatment option; however, pathologically complete remission occurs in approximately only one-third of cases, which thus necessitates new drug development or the application of agents previously used for the treatment of other diseases, such as metformin.

Nicotinamide is the active amide form of vitamin B3 or niacin, a precursor for the synthesis of nicotinamide adenine dinucleotide (NAD+). A recent ONTRAC clinical trial has demonstrated the chemo-preventive effect of nicotinamide in superficial basal-cell carcinomas. In a previous study, we also identified an inhibitory effect of nicotinamide on the development of pre-neoplastic lesions and the progression of differentiated HCC to a high-grade tumor in animal models. However, 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.

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.

Clinical trial identification