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
  • 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.