Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

J Pathol. 2015 Oct;237(2):152-65. doi: 10.1002/path.4562. Epub 2015 Jun 4.


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.

Keywords: HER2; MCT4; PI3K-Akt pathway; breast cancer; lactate; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cell Survival
  • Coculture Techniques
  • Energy Metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Lactic Acid / metabolism
  • MCF-7 Cells
  • Mice, Nude
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction
  • Spheroids, Cellular
  • Time Factors
  • Transfection
  • Tumor Burden


  • Biomarkers, Tumor
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • SLC16A4 protein, human
  • Lactic Acid
  • Phosphatidylinositol 3-Kinase
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Glucose