title: Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies.
abstract: BACKGROUND
  Tryptophan oxidation via the kynurenine pathway is an important mechanism of tumoral immunoresistance. Increased tryptophan metabolism via the serotonin pathway has been linked to malignant progression in breast cancer. In this study, we combined quantitative positron emission tomography (PET) with tumor immunohistochemistry to analyze tryptophan transport and metabolism in breast cancer.
  
  
  METHODS
  Dynamic α-[(11)C]methyl-l-tryptophan (AMT) PET was performed in nine women with stage II-IV breast cancer. PET tracer kinetic modeling was performed in all tumors. Expression of L-type amino acid transporter 1 (LAT1), indoleamine 2,3-dioxygenase (IDO; the initial and rate-limiting enzyme of the kynurenine pathway) and tryptophan hydroxylase 1 (TPH1; the initial enzyme of the serotonin pathway) was assessed by immunostaining of resected tumor specimens.
  
  
  RESULTS
  Tumor AMT uptake peaked at 5-20 min postinjection in seven tumors; the other two cases showed protracted tracer accumulation. Tumor standardized uptake values (SUVs) varied widely (2.6-9.8) and showed a strong positive correlation with volume of distribution values derived from kinetic analysis (P<.01). Invasive ductal carcinomas (n=6) showed particularly high AMT SUVs (range, 4.7-9.8). Moderate to strong immunostaining for LAT1, IDO and TPH1 was detected in most tumor cells.
  
  
  CONCLUSIONS
  Breast cancers show differential tryptophan kinetics on dynamic PET. SUVs measured 5-20 min postinjection reflect reasonably the tracer's volume of distribution. Further studies are warranted to determine if in vivo AMT accumulation in these tumors is related to tryptophan metabolism via the kynurenine and serotonin pathways.
authors.affiliation: PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI 48201, USA. juhasz@pet.wayne.edu
authors.forename: Csaba
authors.initials: C
authors.lastname: Juhász
authors.forename: Zeina
authors.initials: Z
authors.lastname: Nahleh
authors.forename: Ian
authors.initials: I
authors.lastname: Zitron
authors.forename: Diane C
authors.initials: DC
authors.lastname: Chugani
authors.forename: Majid Z
authors.initials: MZ
authors.lastname: Janabi
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mangner
authors.forename: Pulak K
authors.initials: PK
authors.lastname: Chakraborty
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mittal
authors.forename: Otto
authors.initials: O
authors.lastname: Muzik
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007700:Kinetics; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D008875:Middle Aged; D049268:Positron-Emission Tomography; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D027283:Large Neutral Amino Acid-Transporter 1; C020774:alpha-methyltryptophan; D014364:Tryptophan; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase