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Open Access Research article

High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer

Emman Shubbar1*, Khalil Helou2, Anikó Kovács3, Szilárd Nemes2, Shahin Hajizadeh3, Charlotta Enerbäck4 and Zakaria Einbeigi2

Author Affiliations

1 Sahlgrenska Cancer Center, Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-41345, Sweden

2 Sahlgrenska Cancer Center, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-41345, Sweden

3 Pathology section, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, SE-41345, Sweden

4 Department of Clinical and Experimental Medicine, Division of Cell Biology and Dermatology, Linköping University, Linköping, 581 85, Sweden

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BMC Cancer 2013, 13:47  doi:10.1186/1471-2407-13-47

Published: 1 February 2013

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.

Conclusion

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.

Keywords:
GGH; Breast cancer; Primary invasive breast cancer tumors; Prognostic factor; Disease specific survival; Recurrence-free survival