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

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

Author information

1
Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK.
2
Institute of Molecular Systems Biology, ETH Zurich, Switzerland.
3
Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocentre Am Hubland, Würzburg, Germany.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
High Throughput Screening Facility, Cancer Research UK London Research Institute, UK.
6
Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
7
Experimental Histopathology, Cancer Research UK London Research Institute, UK.
8
Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.

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.

KEYWORDS:

HER2; MCT4; PI3K-Akt pathway; breast cancer; lactate; metabolism

PMID:
25965974
DOI:
10.1002/path.4562
[Indexed for MEDLINE]

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