Glutathione S-transferase genotype GSTM1 as a predictor of elevated angiogenic phenotype in patients with early onset breast cancer.
The genes coding for separate isoforms of both the human glutathione-S-transferase class (GST) mu and class theta enzymes (GSTM1 and GSTT1) are polymorphic with a percentage of normal individuals exhibiting a homozygous deletion of the genes. An association between glutathione, proliferation and tumour angiogenesis has been observed. The aim of the present study was to analyse GST polymorphisms and to determine its correlation with the angiogenesis status of the tumoral tissue of patients with breast cancer. For each case, immunohistochemistry of tumour tissue and DNA genotyping by PCR on genomic DNA isolated from blood cells were performed. The mean intratumoral microvessel density (MVD index) was higher for the cases with GSTM1 wild-type genotype in comparison with the cases with the GSTM1-null genotype (89.6 +/- 10.0 vs. 60.9 +/- 6.7; P = 0.022). This was even more evident for women with a breast cancer onset before the age of 35 (106.9 +/- 11.9 vs. 61.8 +/- 9.8; P =0.011). Multivariate logistic regression analysis of GSTM1 and GSTT1 genotypes, histologic grade, axillary node status and age at diagnosis demonstrate the independent association between GSTM1 genotypes and angiogenesis and the association of GSTM1 -wild type genotype with high MVD index (adjusted OR = 5.98, 95% CI 1.28-28.10, P = 0.023). A role of this enzyme in the hypoxia-induced metabolic pathway can be a connection for its association with angiogenesis. Further studies on the enzymatic components of the glutathione biosynthetic pathway in other cancers could define a pharmacogenomic profile of human neoplasia and help identify targets for the development of therapeutic strategies.
Molecular Oncology Unit-Department of Pathology, Instituto Português de Oncologia, Porto, Portugal. mop06210@mail.telepac.pt
Rui
R
Medeiros
Raquel
R
Soares
André
A
Vasconcelos
Fernando
F
Schmitt
Carlos
C
Lopes
D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000502:physiology*; D011237:Predictive Value of Tests
D005982:Glutathione Transferase; C413545:glutathione S-transferase T1