title: Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival.
abstract: Metabolic reprogramming in cancer enhances macromolecule biosynthesis and supports cell survival. Oncogenic drivers affect metabolism by altering distinct metabolic processes and render cancer cells sensitive to perturbations of the metabolic network. This study aimed to identify selective metabolic dependencies in breast cancer by investigating 17 breast cancer cells lines representative of the genetic diversity of the disease. Using a functional screen, we demonstrate here that monocarboxylate transporter 4 (MCT4) is an important regulator of breast cancer cell survival. MCT4 supports pH maintenance, lactate secretion and non-oxidative glucose metabolism in breast cancer cells. Moreover, MCT4 depletion caused an increased dependence of cancer cells on mitochondrial respiration and glutamine metabolism. MCT4 depletion reduced the ability of breast cancer cells to grow in a three-dimensional (3D) matrix or as multilayered spheroids. Moreover, MCT4 expression is regulated by the PI3K-Akt signalling pathway and highly expressed in HER2-positive breast cancers. These results suggest that MCT4 is a potential therapeutic target in defined breast cancer subtypes and reveal novel avenues for combination treatment.
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK.
authors.forename: Franziska
authors.initials: F
authors.lastname: Baenke
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dubuis
authors.affiliation: Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocentre Am Hubland, Würzburg, Germany.
authors.forename: Charlene
authors.initials: C
authors.lastname: Brault
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocentre Am Hubland, Würzburg, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dankworth
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Griffiths
authors.affiliation: High Throughput Screening Facility, Cancer Research UK London Research Institute, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: High Throughput Screening Facility, Cancer Research UK London Research Institute, UK.
authors.forename: Becky
authors.initials: B
authors.lastname: Saunders
authors.affiliation: Experimental Histopathology, Cancer Research UK London Research Institute, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Ros
authors.affiliation: Experimental Histopathology, Cancer Research UK London Research Institute, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: High Throughput Screening Facility, Cancer Research UK London Research Institute, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.affiliation: Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocentre Am Hubland, Würzburg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK.|Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocentre Am Hubland, Würzburg, Germany.|Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D004734:Energy Metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D061986:MCF-7 Cells; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D005947:Glucose; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C406962:SLC16A4 protein, human; C508053:ERBB2 protein, human
keywords: HER2; MCT4; PI3K-Akt pathway; breast cancer; lactate; metabolism