2. Academic Validation
  3. A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer

A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer

  • Cancer Cell. 2015 Dec 14;28(6):743-757. doi: 10.1016/j.ccell.2015.10.013.
Björn von Eyss 1,  Laura A Jaenicke 1,  Roderik M Kortlever 2,  Nadine Royla 3,  Katrin E Wiese 1,  Sebastian Letschert 4,  Leigh-Anne McDuffus 5,  Markus Sauer 4,  Andreas Rosenwald 6,  Gerard I Evan 2,  Stefan Kempa 3,  Martin Eilers 7
Affiliations

Affiliations

  • 1 Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 2 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3 Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
  • 4 Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 5 Histopathology and ISH Core Facility, Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, UK.
  • 6 Institute of Pathology, University of Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Straße 6, 97080 Würzburg, Germany.
  • 7 Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Straße 6, 97080 Würzburg, Germany. Electronic address: [email protected].
PMID: 26678338 DOI: 10.1016/j.ccell.2015.10.013
Abstract

In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a Phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors.

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