title: A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer.
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.
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jaenicke
authors.affiliation: 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.
authors.forename: Roderik M
authors.initials: RM
authors.lastname: Kortlever
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Royla
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Wiese
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Letschert
authors.affiliation: Histopathology and ISH Core Facility, Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, UK.
authors.forename: Leigh-Anne
authors.initials: LA
authors.lastname: McDuffus
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sauer
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: 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.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kempa
authors.affiliation: 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: martin.eilers@biozentrum.uni-wuerzburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D019070:Cell Lineage; D019295:Computational Biology; D030541:Databases, Genetic; D004789:Enzyme Activation; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics; D010641:Phenotype; D010739:Phospholipase D / Q000096:biosynthesis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D014162:Transfection; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055372:AMP-Activated Protein Kinases; D010739:Phospholipase D