title: Response to trastuzumab by HER2 expressing breast tumour xenografts is accompanied by decreased Hexokinase II, glut1 and [18F]-FDG incorporation and changes in 31P-NMR-detectable phosphomonoesters.
abstract: OBJECTIVE
  Trastuzumab, effective in about 15 % of women with breast cancer, downregulates signalling through the Akt/PI3K and MAPK pathways. These pathways modulate glucose and phospholipid metabolism which can be monitored by [(18)F]FDG-PET and (31)P-NMR spectroscopy, respectively. Here, the relationship between response of HER-2 overexpressing tumours and changes in [(18)F]-FDG incorporation and (31)P-NMR-detectable phosphomonoesters were examined.
  
  
  METHODS
  Xenografts derived from HER2-overexpressing MDA-MB-453 human breast tumour cells were grown in SCID mice, treated with trastuzumab for 15 days, then [(18)F]-FDG uptake determined and (31)P-NMR carried out on chemical extracts of the tumours. Western blots were carried out to determine protein expression of Hexokinase II and glut1.
  
  
  RESULTS
  [(18)F]-FDG incorporation, Hexokinase II and glut1 protein expression and the concentration of phosphocholine and phosphoethanolamine in chemical extracts subjected to (31)P-NMR were significantly decreased in the xenografts in the trastuzumab-treated mice compared with xenografts from the PBS-injected group.
  
  
  CONCLUSIONS
  Changes in FDG incorporation and (31)P-NMR spectral changes can accompany response of HER2-expressing breast cancer xenografts to trastuzumab. This is the first study to show parallel changes in [(18)F]FDG- and (31)P-NMR-detectable metabolites accompany response to targeted anticancer treatment.
authors.affiliation: Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Biomedical Physics Building, Foresterhill, Aberdeen AB25 2ZD, UK. t.smith@abdn.ac.uk
authors.forename: Tim A D
authors.initials: TA
authors.lastname: Smith
authors.forename: M Virginia C L
authors.initials: MV
authors.lastname: Appleyard
authors.forename: Sheila
authors.initials: S
authors.lastname: Sharp
authors.forename: Ian N
authors.initials: IN
authors.lastname: Fleming
authors.forename: Karen
authors.initials: K
authors.lastname: Murray
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000032:analysis*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; D051272:Glucose Transporter Type 1; D006593:Hexokinase; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human