title: Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer.
abstract: OBJECTIVE
  Cancer cells have altered metabolism, with increased glucose uptake, glycolysis, and biomass production. This study conducted genomic and metabolomic analyses to elucidate how tumor and stromal genomic characteristics influence tumor metabolism.
  
  
  METHODS
  Thirty-three breast tumors and six normal breast tissues were analyzed by gene expression microarray and by mass spectrometry for metabolites. Gene expression data and clinical characteristics were evaluated in association with metabolic phenotype. To evaluate the role of stromal interactions in altered metabolism, cocultures were conducted using breast cancer cells and primary cancer-associated fibroblasts (CAF).
  
  
  RESULTS
  Across all metabolites, unsupervised clustering resulted in two main sample clusters. Normal breast tissue and a subset of tumors with less aggressive clinical characteristics had lower levels of nucleic and amino acids and glycolysis byproducts, whereas more aggressive tumors had higher levels of these Warburg-associated metabolites. While tumor-intrinsic subtype did not predict metabolic phenotype, metabolic cluster was significantly associated with expression of a wound response signature. In cocultures, CAFs from basal-like breast cancers increased glucose uptake and basal-like epithelial cells increased glucose oxidation and glycogen synthesis, suggesting interplay of stromal and epithelial phenotypes on metabolism. Cytokine arrays identified hepatocyte growth factor (HGF) as a potential mediator of stromal-epithelial interaction and antibody neutralization of HGF resulted in reduced expression of glucose transporter 1 (GLUT1) and decreased glucose uptake by epithelium.
  
  
  CONCLUSIONS
  Both tumor/epithelial and stromal characteristics play important roles in metabolism. Warburg-like metabolism is influenced by changes in stromal-epithelial interactions, including altered expression of HGF/Met pathway and GLUT1 expression.
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Heather Ann
authors.initials: HA
authors.lastname: Brauer
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.forename: Patricia
authors.initials: P
authors.lastname: Casbas-Hernandez
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Lang
authors.forename: Erick
authors.initials: E
authors.lastname: Romàn-Pèrez
authors.forename: Monica
authors.initials: M
authors.lastname: D'Arcy
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D051272:Glucose Transporter Type 1; D017228:Hepatocyte Growth Factor; D005947:Glucose