Format

Send to

Choose Destination
Front Genet. 2019 May 7;10:420. doi: 10.3389/fgene.2019.00420. eCollection 2019.

Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer.

Author information

1
Department of Bioengineering, Marmara University, Istanbul, Turkey.
2
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
3
Department of Bioengineering, Istanbul Medeniyet University, Istanbul, Turkey.
4
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
5
Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, United States.
6
Faculty of Dentistry, Oral and Craniofacial Sciences, Centre for Host-Microbiome Interactions, King's College London, London, United Kingdom.
7
Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.

Abstract

Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.

KEYWORDS:

basal subtype; breast cancer; drug repositioning; non-cancer therapeutics; personalized metabolic models; repurposing

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center