Angiogenesis signaling in breast cancer models is induced by hexachlorobenzene and chlorpyrifos, pesticide ligands of the aryl hydrocarbon receptor

LORENA ZÁRATE; CAROLINA PONTILLO; ALEJANDRO ESPAÑOL; NOELIA MIRET; FLORENCIA CHIAPPINI; CLAUDIA COCCA; LAURA ALVAREZ; DIANA KLEIMAN DE PISAREV; MARÍA ELENA SALES; ANDREA RANDI

TOXICOLOGY AND APPLIED PHARMACOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020 vol. 401

0041-008X

Breast cancer incidence is increasing globally and pesticidesexposure may impact risk of developing this disease. Hexachlorobenzene(HCB) and chlorpyrifos (CPF) act as endocrine disruptors, inducingproliferation in breast cancer cells. Vascular endothelial growth factor-A (VEGF-A), cyclooxygenase-2 (COX-2) and nitric oxide (NO) are associatedwith angiogenesis. Our aim was to evaluate HCB and CPF action, both weakaryl hydrocarbon receptor (AhR) ligands, on angiogenesis in breast cancermodels. We used: (1) in vivo xenograft model with MCF-7 cells, (2) invitro breast cancer model with MCF-7, and (3) in vitro neovasculogenesismodel with endothelial cells exposed to conditioned medium from MCF-7.Results show that HCB (3 mg/kg) and CPF (0.1 mg/kg) stimulated vasculardensity in the in vivo model. HCB and CPF low doses enhanced VEGF-A andCOX-2 expression, accompanied by increased levels of nitric oxidesynthases (NOS), and NO release in MCF-7. HCB and CPF high dosesintensified VEGF-A and COX-2 levels but rendered different effects onNOS, however, both pesticides reduced NO production. Moreover, our dataindicate that HCB and CPF-induced VEGF-A expression is mediated byestrogen receptor and NO, while the increase in COX-2 is through AhR andNO pathways in MCF-7. In conclusion, we demonstrate that HCB and CPFenvironmental concentrations stimulate angiogenic switch in vivo.Besides, pesticides induce VEGF-A and COX-2 expression, as well as NOproduction in MCF-7, promoting tubulogenesis in endothelial cells. These findings show that pesticide exposure could stimulate angiogenesis, a process that has been demonstrated to contribute to breast cancerprogression.