Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival Journal Article
| Authors: | Baenke, F.; Dubuis, S.; Brault, C.; Weigelt, B.; Dankworth, B.; Griffiths, B.; Jiang, M.; Mackay, A.; Saunders, B.; Spencer-Dene, B.; Ros, S.; Stamp, G.; Reis-Filho, J. S.; Howell, M.; Zamboni, N.; Schulze, A. |
| Article 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. © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| Keywords: | signal transduction; protein kinase b; controlled study; human tissue; cancer growth; nonhuman; protein function; mouse; metabolism; animal tissue; cell survival; breast cancer; protein depletion; animal experiment; animal model; rna interference; in vivo study; in vitro study; phosphatidylinositol 3 kinase; gene expression regulation; cancer cell; glucose; homeostasis; cell metabolism; oxidation reduction reaction; glutamine; her2; lactic acid; mitochondrial respiration; glucose metabolism; aerobic metabolism; amino acid metabolism; lactate; cell ph; tumor spheroid; human; priority journal; article; breast cancer cell line; monocarboxylate transporter 4; mct4; pi3k-akt pathway |
| Journal Title: | Journal of Pathology |
| Volume: | 237 |
| Issue: | 2 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2015-10-01 |
| Start Page: | 152 |
| End Page: | 165 |
| Language: | English |
| DOI: | 10.1002/path.4562 |
| PROVIDER: | scopus |
| PUBMED: | 25965974 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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