Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
Journal article, 2019

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.

repurposing

personalized metabolic models

basal subtype

drug repositioning

non-cancer therapeutics

breast cancer

Author

Beste Turanli

Royal Institute of Technology (KTH)

Istanbul Medeniyet University

Marmara University

Kubra Karagoz

Rutgers Cancer Institute of New Jersey

Gholamreza Bidkhori

Royal Institute of Technology (KTH)

Raghu Sinha

Penn State College of Medicine

Michael L. Gatza

Rutgers Cancer Institute of New Jersey

Mathias Uhlen

Royal Institute of Technology (KTH)

Adil Mardinoglu

Science for Life Laboratory (SciLifeLab)

King's College London

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Kazim Yalcin Arga

Marmara University

Frontiers in Genetics

16648021 (eISSN)

Vol. 10 MAY 420

Subject Categories

Surgery

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Cancer and Oncology

DOI

10.3389/fgene.2019.00420

More information

Latest update

10/10/2022