1. Hexachlorobenzene promotes angiogenesis in an in vivo model of breast cancer and vasculogenesis in vitro in the human endothelial cell line HMEC-1

PONTILLO C; ESPAÑOL A; CHIAPPINI F; MIRET N; COCCA C; ALVAREZ N; KLEIMAN D; SALES ME; RANDI A

Congreso; 50th Congress of the European Societies of Toxicology.; 2014

Exposure to environmental pollutants may alter proangiogenic ability and promotes tumor growth. Hexachlorobenzene (HCB) is an organochlorine pesticide found in maternal milk and it is a weak ligand of the aryl hydrocarbon receptor (AhR). We have demonstrated that HCB induces proliferation, migration and invasion in human breast cancer cells, as well as tumor growth and metastasis in vivo. Here, we examined the action of HCB on breast cancer angiogenesis. We observed that HCB (3 and 30 mg/kg body weight) stimulated angiogenesis (20.42% falta error) and increased VEGF expression (90.11% falta error) in a xenograft model obtained by inoculating the human breast cancer cell line, MDA-MB-231 in nude mice. When HMEC-1cells were exposed to HCB (0, 0.005, 0.05, 0.5 and 5 µM) for 15 min, 18, 24 and 48 h, it enhances cyclooxygenase-2 (COX-2) (76,106,91,62%), as well as VEGF expression (50,45,47,50%), and AhR protein levels at 0.05, 0.5 and 5 µM (100,139,160%). Besides, the pesticide increases VEGFR2 expression at 0.5 µM (39%), and activates their downstream pathways p38 (68,53,68%) and ERK1/2 (137,127,164%) at 0.05, 0.5 and 5 µM. On the other hand, HCB didn´t affect cell proliferation however increases migration (35, 30, 57, 61%) and neovasculogenesis (82,77,123,127%). The pretreatment of cells with inhibitors of AhR, COX-2 and VEGFR2 suppresses HCB-induced cell migration and neovasculogenesis. In conclusion, our results demonstrate that HCB promotes angiogenesis in vivo and in vitro. HCB-induced cell migration and tubulogenesis are mediated by AhR, COX-2 and VEGFR2 proteins in HMEC-1. These findings may help to understand the association among HCB exposure, angiogenesis and mammary carcinogenesis.