Hexachlorobenzene promotes angiogenesis in vivo, in a breast cancer model and neovasculogenesis in vitro, in the human endothelial cell line HMEC-1

PONTILLO CA; ESPAÑOL A; CHIAPPINI F; MIRET N; COCCA C; ALVAREZ L; KLEIMAN DL DE PISAREV; SALES ME; RANDI AS

Edimburgo

Congreso; EUROTOX; 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 ligand of the aryl hydrocarbon receptor (AhR). We 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 HCB action on breast cancer angiogenesis. We observed that HCB (3 and 30 mg/kg body weight) stimulates angiogenesis (42%,p<0.001) and increases vascular endothelial growth factor (VEGF) expression (110%,p<0.01) in a xenograft model obtained by inoculating the human breast cancer cell line, MDA-MB-231 in nude mice. When HMEC-1 cells were exposed to HCB (0.005, 0.05, 0.5 and 5 µM), we observed that the pesticide increases cyclooxygenase-2 (COX-2) (106%,p<0.01) as well as VEGF expression (50%,p<0.01), at all assayed doses, while increases AhR protein levels in a dose-dependent manner. Besides, we found that only 0.5 µM of the pesticide increases VEGFR2 expression (39%,p<0.01), and HCB 0.05, 0.5 and 5 µM activates their downstream pathways p38 (68%,p<0.01) and ERK1/2 (164%,p<0.01). Meanwhile, HCB increases cell migration and neovasculogenesis in a dose-dependent manner, without affecting cell proliferation. These effects are suppresses with cell pretreatment with inhibitors of AhR, COX-2 and VEGFR2. 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.