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Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
KTH, Centres, Science for Life Laboratory, SciLifeLab.
Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA..
KTH, Centres, Science for Life Laboratory, SciLifeLab.
Penn State Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA..
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2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 420Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 10, article id 420
Keywords [en]
breast cancer, drug repositioning, non-cancer therapeutics, repurposing, basal subtype, personalized metabolic models
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-252378DOI: 10.3389/fgene.2019.00420ISI: 000467463700001Scopus ID: 2-s2.0-85067884608OAI: oai:DiVA.org:kth-252378DiVA, id: diva2:1337957
Note

QC 20190718

Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-18Bibliographically approved

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Bidkhori, GholamrezaUhlén, MathiasMardinoglu, Adil

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