Model-based unsupervised learning informs metformin-induced cell-migration inhibition through an AMPK-independent mechanism in breast cancer.

Journal: Oncotarget
PMID: 28423712

Abstract

We demonstrate that model-based unsupervised learning can uniquely discriminate single-cell subpopulations by their gene expression distributions, which in turn allow us to identify specific genes for focused functional studies. This method was applied to MDA-MB-231 breast cancer cells treated with the antidiabetic drug metformin, which is being repurposed for treatment of triple-negative breast cancer. Unsupervised learning identified a cluster of metformin-treated cells characterized by a significant suppression of 230 genes (p-value < 2E-16). This analysis corroborates known studies of metformin action: a) pathway analysis indicated known mechanisms related to metformin action, including the citric acid (TCA) cycle, oxidative phosphorylation, and mitochondrial dysfunction (p-value < 1E-9); b) 70% of these 230 genes were functionally implicated in metformin response; c) among remaining lesser functionally-studied genes for metformin-response was CDC42, down-regulated in breast cancer treated with metformin. However, CDC42's mechanisms in metformin response remained unclear. Our functional studies showed that CDC42 was involved in metformin-induced inhibition of cell proliferation and cell migration mediated through an AMPK-independent mechanism. Our results points to 230 genes that might serve as metformin response signatures, which needs to be tested in patients treated with metformin and, further investigation of CDC42 and AMPK-independence's role in metformin's anticancer mechanisms.

Authors

  • Arjun P Athreya
    Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
  • Krishna R Kalari
    All authors: Mayo Clinic, Rochester, MN.
  • Junmei Cairns
    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
  • Alan J Gaglio
    Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
  • Quin F Wills
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Nifang Niu
    Department of Pathology, University of Chicago, Chicago, IL, USA.
  • Richard Weinshilboum
    Department of Pharmacology, Mayo Clinic, Rochester, MN, USA.
  • Ravishankar K Iyer
    Coordinated Science Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
  • Liewei Wang
    All authors: Mayo Clinic, Rochester, MN.

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