Molecular pathways: dysregulated glutamatergic signaling pathways in cancer.
ABSTRACT The neurotransmitter glutamate interacts with glutamate receptor proteins, leading to the activation of multiple signaling pathways. Dysfunction in the glutamatergic signaling pathway is well established as a frequent player in diseases such as schizophrenia, Alzheimer disease, and brain tumors (gliomas). Recently, aberrant functioning of this pathway has also been shown in melanoma. In both glioma and melanoma, glutamate secretion stimulates tumor growth, proliferation, and survival through activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways. In the future, extracellular glutamate levels and glutamatergic signaling may serve as biological markers for tumorigenicity and facilitate targeted therapy for melanoma. .
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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 gamma-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.BMC Cancer 02/2013; 13(1):47. · 3.33 Impact Factor