title: Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.
abstract: BACKGROUND
  Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.
  
  
  METHODS
  High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.
  
  
  RESULTS
  The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.
  
  
  CONCLUSIONS
  Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Sjaak.vanAsten@radboudumc.nl.
authors.forename: Jack J A
authors.initials: JJ
authors.lastname: van Asten
authors.affiliation: Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. muhammad.r.vettukattil@ntnu.no.
authors.forename: Riyas
authors.initials: R
authors.lastname: Vettukattil
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. T.Buckle@lumc.nl.|Department of Molecular Pathology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek hospital (NKI-AvL), Amsterdam, The Netherlands. T.Buckle@lumc.nl.
authors.forename: Tessa
authors.initials: T
authors.lastname: Buckle
authors.affiliation: Department of Molecular Pathology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek hospital (NKI-AvL), Amsterdam, The Netherlands. s.rottenberg@nki.nl.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. F.W.B.van_Leeuwen@lumc.nl.
authors.forename: Fijs
authors.initials: F
authors.lastname: van Leeuwen
authors.affiliation: Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. tone.f.bathen@ntnu.no.
authors.forename: Tone F
authors.initials: TF
authors.lastname: Bathen
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Arend.Heerschap@radboudumc.nl.
authors.forename: Arend
authors.initials: A
authors.lastname: Heerschap
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002794:Choline / Q000378:metabolism*; D000077143:Docetaxel; D019398:Genes, BRCA1; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D066244:Proton Magnetic Resonance Spectroscopy; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel; D002794:Choline