title: High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer.
abstract: BACKGROUND
  Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients.
  
  
  METHODS
  The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models.
  
  
  RESULTS
  The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues.
  
  
  CONCLUSIONS
  These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.
authors: Sahlgrenska Cancer Center, Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-41345, Sweden. emman.shubbar@gu.se
authors: Emman
authors: E
authors: Shubbar
authors: Khalil
authors: K
authors: Helou
authors: Anikó
authors: A
authors: Kovács
authors: Szilárd
authors: S
authors: Nemes
authors: Shahin
authors: S
authors: Hajizadeh
authors: Charlotta
authors: C
authors: Enerbäck
authors: Zakaria
authors: Z
authors: Einbeigi
mesh_terms: D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018275:Carcinoma, Lobular / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002352:Carrier Proteins / Q000032:analysis; D016009:Chi-Square Distribution; D003593:Cytoplasm / Q000201:enzymology; D049308:Dioxygenases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000032:analysis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D035381:TATA-Binding Protein Associated Factors / Q000032:analysis; D013997:Time Factors; D035362:Transcription Factor TFIID / Q000032:analysis; D015854:Up-Regulation; D011623:gamma-Glutamyl Hydrolase / Q000032:analysis* / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000032:analysis; D000099224:p300-CBP-Associated Factor; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D049308:Dioxygenases; D009687:Nuclear Proteins; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D011623:gamma-Glutamyl Hydrolase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099252:Fatty Acid Amide Hydrolases; C100838:TAF5 protein, human; C105340:PIR protein, human
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