Body mass index and γ-glutamyl transferase expression in normal and cancerous breast tissue.
Coradini Danila,Gambazza Simone,Oriana Saro,Ambrogi Federico
Breast cancer (Tokyo, Japan)
BACKGROUND:Localized to cell membrane, γ-glutamyl transferase (GGT) is a reliable marker for the evaluation of cell distress occurring in several pathological conditions including obesity, metabolic syndrome, and cancer. In particular, high GGT serum levels are associated with breast cancer incidence and progression. METHODS:The tissue expression of GGT1, the gene coding for GGT, was investigated in silico in a large case series of paired samples of breast cancer and adjacent histologically normal (HN) tissue, and in a collection of healthy breast tissues from reduction mammoplasty. The association of GGT1 with patient's body mass index (BMI), and the relationship between GGT1 and a panel of genes involved in apoptosis, IGF-1 signaling, or coding for adipokines and adipokine receptors were also investigated. RESULTS:GGT1 expression was significantly higher in tumor than in the adjacent HN tissue (P = 0.0002). Unexpectedly, the expression of GGT1 was inversely associated with BMI in normal and HN tissue, whereas no correlation was found in cancerous tissue. In all tissues, GGT1 correlated positively with TP53 and negatively with BCL2 and LEPR, whereas only in normal and HN tissue GGT1 correlated positively with IGF1R. The linear regression model, adjusted for BMI, showed no confounding effect on any correlation, except for the correlation of GGT1 with LEPR in normal tissue from healthy women. CONCLUSIONS:Even if present results provide interesting insights on the still elusive mechanism(s) underlying the association between obesity and epithelial cell proliferation, possibly promoting neoplastic transformation, such relationship deserves further investigation in other independent datasets.
The human gamma-glutamyltransferase gene family.
Heisterkamp Nora,Groffen John,Warburton David,Sneddon Tam P
Assays for gamma-glutamyl transferase (GGT1, EC 188.8.131.52) activity in blood are widely used in a clinical setting to measure tissue damage. The well-characterized GGT1 is an extracellular enzyme that is anchored to the plasma membrane of cells. There, it hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors. As such, it has a critical function in the metabolism of glutathione and in the conversion of the leukotriene LTC4 to LTD4. GGT deficiency in man is rare and for the few patients reported to date, mutations in GGT1 have not been described. These patients do secrete glutathione in urine and fail to metabolize LTC4. Earlier pre-genome investigations had indicated that besides GGT1, the human genome contains additional related genes or sequences. These sequences were given multiple different names, leading to inconsistencies and confusion. Here we systematically evaluated all human sequences related to GGT1 using genomic and cDNA database searches and identified thirteen genes belonging to the extended GGT family, of which at least six appear to be active. In collaboration with the HUGO Gene Nomenclature Committee (HGNC) we have designated possible active genes with nucleotide or amino acid sequence similarity to GGT1, as GGT5 (formerly GGL, GGTLA1/GGT-rel), GGT6 (formerly rat ggt6 homologue) and GGT7 (formerly GGTL3, GGT4). Two loci have the potential to encode only the light chain portion of GGT and have now been designated GGTLC1 (formerly GGTL6, GGTLA4) and GGTLC2. Of the five full-length genes, three lack of significant nucleotide sequence homology but have significant (GGT5, GGT7) or very limited (GGT6) amino acid similarity to GGT1 and belong to separate families. GGT6 and GGT7 have not yet been described, raising the possibility that leukotriene synthesis, glutathione metabolism or gamma-glutamyl transfer is regulated by their, as of yet uncharacterized, enzymatic activities. In view of the widespread clinical use of assays that measure gamma-glutamyl transfer activity, this would appear to be of significant interest.