Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy

Gary Guishan Xiao, Bing Sen Zhou, George Somlo, Jana Portnow, Agnes Juhasz, Frank Un, Helen K Chew, David R Gandara, Yun Yen

Research output: Contribution to journalArticle

9 Citations (Scopus)

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. Materials and 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 mlz 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/SKP2 directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)151-160
Number of pages10
JournalCancer Genomics and Proteomics
Volume5
Issue number3-4
StatePublished - May 2008

Fingerprint

Biomarkers
Ribonucleotide Reductases
Breast Neoplasms
Ionization
Mass spectrometry
Proteins
Phosphorothioate Oligonucleotides
F-Box Proteins
Antisense Oligonucleotides
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Liquid chromatography
Multiple Drug Resistance
Therapeutics
Tandem Mass Spectrometry
Liquid Chromatography
Pharmaceutical Preparations
Proteomics
Real-Time Polymerase Chain Reaction
Desorption
Mass Spectrometry

Keywords

  • Biomarker
  • Breast cancer
  • Proteomics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research
  • Biochemistry

Cite this

Xiao, G. G., Zhou, B. S., Somlo, G., Portnow, J., Juhasz, A., Un, F., ... Yen, Y. (2008). Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy. Cancer Genomics and Proteomics, 5(3-4), 151-160.

Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy. / Xiao, Gary Guishan; Zhou, Bing Sen; Somlo, George; Portnow, Jana; Juhasz, Agnes; Un, Frank; Chew, Helen K; Gandara, David R; Yen, Yun.

In: Cancer Genomics and Proteomics, Vol. 5, No. 3-4, 05.2008, p. 151-160.

Research output: Contribution to journalArticle

Xiao, GG, Zhou, BS, Somlo, G, Portnow, J, Juhasz, A, Un, F, Chew, HK, Gandara, DR & Yen, Y 2008, 'Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy', Cancer Genomics and Proteomics, vol. 5, no. 3-4, pp. 151-160.
Xiao, Gary Guishan ; Zhou, Bing Sen ; Somlo, George ; Portnow, Jana ; Juhasz, Agnes ; Un, Frank ; Chew, Helen K ; Gandara, David R ; Yen, Yun. / Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy. In: Cancer Genomics and Proteomics. 2008 ; Vol. 5, No. 3-4. pp. 151-160.
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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. Materials and 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 mlz 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/SKP2 directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7. Conclusion: 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.",
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