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The genes coding for separate isoforms of both the human glutathione-S-transferase class (GST)muand 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 GSTpolymorphisms 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 GSTM1wild-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 GSTM1and GSTT1genotypes, histologic grade, axillary node status and age at diagnosis demonstrate the independent association between GSTM1genotypes 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.

It is widely established that angiogenesis is required during tumor progression. Emerging data, suggests that estrogens can mediate endothelial proliferation and differentiation. We investigated the role of estrogens in the formation and stabilization of capillary-like structures, and identified 17β-estradiol-driven pathways involved in vessel assembly. We show that estrogens induce MCF7 breast cancer cells to secrete TGFβ1. In addition, TGFβcross talks with EGFR signaling pathway with concomitant up-regulation of EGFR ligand, TGFα, promoting cord-like formations in HUVEC cultures. The action of 17β-estradiol was not restricted to endothelium, since 17β-estradiol also stimulated recovery and migration of a smooth muscle cell line (FLTR) to injured areas again by the cross talk between these two signaling pathways. Finally, given the relevant role of 17β-estradiol in vessel stabilization, co-cultures of HUVEC and FLTR cells were established in the presence of 17β-estradiol or TGFβ1. By blocking TGFβor EGFR signaling, we demonstrate that 17β-estradiol promoted vessel stabilization through the interplay of TGFβ1 and EGFR signaling transduction pathways. Our data suggest that estrogen mediates endothelial cell stabilization and vessel assembly. These vessel protective effects involve TGFβ1 and EGFR signaling transduction pathways.