Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
Artikel i vetenskaplig tidskrift, 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.

personalized metabolic models

drug repositioning

non-cancer therapeutics

repurposing

basal subtype

breast cancer

Författare

Beste Turanli

Istanbul Medenryet Univ

Kungliga Tekniska Högskolan (KTH)

Marmara Universitesi

Kubra Karagoz

Rutgers Cancer Institute of New Jersey

Gholamreza Bidkhori

Kungliga Tekniska Högskolan (KTH)

Raghu Sinha

Penn State College of Medicine

Michael L. Gatza

Rutgers Cancer Institute of New Jersey

Mathias Uhlen

Kungliga Tekniska Högskolan (KTH)

Adil Mardinoglu

King's College London

Chalmers, Biologi och bioteknik, Systembiologi

Science for Life Laboratory (SciLifeLab)

Kazim Yalcin Arga

Marmara Universitesi

Frontiers in Genetics

1664-8021 (ISSN)

Vol. 10 420

Ämneskategorier

Kirurgi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Cancer och onkologi

DOI

10.3389/fgene.2019.00420

Mer information

Senast uppdaterat

2019-11-04