title: Hexachlorobenzene promotes angiogenesis in vivo, in a breast cancer model and neovasculogenesis in vitro, in the human microvascular endothelial cell line HMEC-1.
abstract: Exposure to environmental pollutants may alter proangiogenic ability and promotes tumor growth. Hexachlorobenzene (HCB) is an organochlorine pesticide found in maternal milk and in lipid foods, and a weak ligand of the aryl hydrocarbon receptor (AhR). HCB induces migration and invasion in human breast cancer cells, as well as tumor growth and metastasis in vivo. In this study, we examined HCB action on angiogenesis in mammary carcinogenesis. HCB stimulates angiogenesis and increases vascular endothelial growth factor (VEGF) expression in a xenograft model with the human breast cancer cell line MDA-MB-231. Human microvascular endothelial cells HMEC-1 exposed to HCB (0.005, 0.05, 0.5 and 5μM) showed an increase in cyclooxygenase-2 (COX-2) and VEGF protein expression involving AhR. In addition, we found that HCB enhances VEGF-Receptor 2 (VEGFR2) expression, and activates its downstream pathways p38 and ERK1/2. HCB induces cell migration and neovasculogenesis in a dose-dependent manner. Cells pretreatment with AhR, COX-2 and VEGFR2 selective inhibitors, suppressed these effects. In conclusion, our results show that HCB promotes angiogenesis in vivo and in vitro. HCB-induced cell migration and tubulogenesis are mediated by AhR, COX-2 and VEGFR2 in HMEC-1. These findings may help to understand the association among HCB exposure, angiogenesis and mammary carcinogenesis.
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: caroponti@hotmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pontillo
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Paraguay 2155, 16° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: aespan_1999@yahoo.com.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Español
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina; Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Paraguay 2155, 16° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: florenciachiappini@hotmail.com.
authors.forename: Florencia
authors.initials: F
authors.lastname: Chiappini
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: noeliamiret@hotmail.com.ar.
authors.forename: Noelia
authors.initials: N
authors.lastname: Miret
authors.affiliation: Laboratorio de Radioisótopos, Departamento de Físico-Matemática, Facultad de Farmacia y Bioquímica, Junín 954, subsuelo (CP1113), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: cm_cocca@hotmail.com.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocca
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: laura6alvarez@yahoo.com.ar.
authors.forename: Laura
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: dianakleiman@yahoo.com.ar.
authors.forename: Diana
authors.initials: D
authors.lastname: Kleiman de Pisarev
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Paraguay 2155, 16° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: malegazpio@yahoo.com.ar.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Sales
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Paraguay 2155, 5° piso, (CP1121), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: andybiol@yahoo.com.ar.
authors.forename: Andrea Silvana
authors.initials: AS
authors.lastname: Randi
mesh_terms: D001943:Breast Neoplasms / Q000098:blood supply* / Q000473:pathology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D006581:Hexachlorobenzene / Q000633:toxicity*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
chemical_list: D005659:Fungicides, Industrial; D018336:Receptors, Aryl Hydrocarbon; D042461:Vascular Endothelial Growth Factor A; D006581:Hexachlorobenzene; D051546:Cyclooxygenase 2; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Aryl hydrocarbon receptor; Breast cancer; HMEC-1 cells; Hexachlorobenzene; Vascular endothelial growth factor