The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

Elizabeth A Wellberg; Stevi Johnson; Jessica Finlay-Schultz; Andrew S Lewis; Kristina L Terrell; Carol A Sartorius; E. Dale Abel; William J Muller; Steven M Anderson

doi:10.1186/s13058-016-0795-0

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The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

Journal article

Open access

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

Elizabeth A Wellberg, Stevi Johnson, Jessica Finlay-Schultz, Andrew S Lewis, Kristina L Terrell, Carol A Sartorius, E. Dale Abel, William J Muller and Steven M Anderson

Breast cancer research : BCR, Vol.18(1), pp.131-131

2016

DOI: 10.1186/s13058-016-0795-0

PMCID: PMC5168867

PMID: 27998284

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Abstract

Background Altered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis. Methods To determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 Flox/Flox (GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC-GLUT1Flox/Flox mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis. Results All of the NIC-GLUT1+/+ mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Flox mouse and 1 NIC-GLUT1Flox/+ mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1Flox/+ mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress. Conclusions This study demonstrates a strict requirement for GLUT1 in the early stages of mammary tumorigenesis in vitro and in vivo. While metabolic adaptation has emerged as a hallmark of cancer, our data indicate that early tumor cells rely heavily on glucose and highlight the potential for glucose restriction as a breast cancer preventive strategy.

Breast Cancer

GLUT1

ERBB2

Slc2a1

Glucose

Mammary tumor

HER2

MMTV-NIC

Neu

Details

Title: Subtitle: The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis
Creators: Elizabeth A Wellberg - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Stevi Johnson - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Jessica Finlay-Schultz - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Andrew S Lewis - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Kristina L Terrell - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Carol A Sartorius - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
E. Dale Abel - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 USA
William J Muller - Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3 Canada
Steven M Anderson - Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO 80045 USA
Resource Type: Journal article
Publication Details: Breast cancer research : BCR, Vol.18(1), pp.131-131
DOI: 10.1186/s13058-016-0795-0
PMID: 27998284
PMCID: PMC5168867
NLM abbreviation: Breast Cancer Res
ISSN: 1465-5411
eISSN: 1465-542X
Publisher: BioMed Central; London
Grant note: R01-CA138482 / ;
Language: English
Date published: 2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025270402771

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