title: Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy.
abstract: BACKGROUND
  The expression and activity of ribonucleotide reductase (RR) has been associated with resistance to multiple drugs in human cancer. The use of antisense oligonucleotide drug, GTI-2040, a 20-mer phosphorothioate oligonucleotide complemented to the human RR M2 subunit mRNA, represents an effective strategy for inhibiting RR. The increased specificity due to the anti-resistance effect of GTI-2040 may also lead to a more favorable therapeutic outcome.
  
  
  METHODS
  To understand the molecular mechanism underlying RR inhibition, patients' blood samples were analyzed using multiple dimensional proteomics technology via matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry.
  
  
  RESULTS
  A major difference occurred at 5k m/z in the MALDI profile, which appeared only in the non-responsive group and diminished after GTI-2040 treatment. This specific peptide peak remained at the basal level in responsive patients. The peak was identified to represent the F-box/LLR-repeat protein 17 (FBXL17) through nanoelectrospray ionization liquid chromatography-tandem mass spectrometry (nanoESI LC-MS/MS). Further characterization revealed that FBXL17 [corrected] directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7.
  
  
  CONCLUSIONS
  Validation of this protein using real-time RT-PCR indicates the F-box protein 17 (FBXL17) can serve as a therapeutic target and surrogate marker for breast cancer therapy.
authors.affiliation: Department of Clinical & Molecular Pharmacology, City of Hope National Cancer Center, Duarte, CA 91010-3000, USA.
authors.forename: Gary Guishan
authors.initials: GG
authors.lastname: Xiao
authors.forename: Bing-Sen
authors.initials: BS
authors.lastname: Zhou
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Jana
authors.initials: J
authors.lastname: Portnow
authors.forename: Agnes
authors.initials: A
authors.lastname: Juhasz
authors.forename: Frank
authors.initials: F
authors.lastname: Un
authors.forename: Helen
authors.initials: H
authors.lastname: Chew
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017931:DNA Primers; D044783:F-Box Proteins; C532335:FBXL17 protein, human; D009838:Oligodeoxyribonucleotides; C464617:GTI2040