title: The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis.
abstract: 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.
  
  
  
  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 Slc2a1Flox/Flox(GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC-GLUT1Flox/Floxmice. 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.
  
  
  
  All of the NIC-GLUT1+/+mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Floxmouse 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.
  
  
  
  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.
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA. Elizabeth.wellberg@ucdenver.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wellberg
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA.
authors.forename: Stevi
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Finlay-Schultz
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lewis
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA.
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Terrell
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA.|Program in Cancer Biology, MS 8401, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
authors.affiliation: Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Rosalind and Morris Goodman Cancer Center, McGill University, Montreal, Quebec, H3A 1A3, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Pathology, MS 8401, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Box 8104, Aurora, CO, 80045, USA. steve.anderson@ucdenver.edu.|Program in Cancer Biology, MS 8401, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. steve.anderson@ucdenver.edu.|Program in Molecular Biology, MS 8401, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. steve.anderson@ucdenver.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D005947:Glucose; D051272:Glucose Transporter Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Breast cancer; ERBB2; GLUT1; Glucose; HER2; MMTV-NIC; Mammary tumor; Neu; Slc2a1