ABOUT PESTICIDES AND OTHER DEMONS: INDUCTION OF TUMOR ANGIOGENESIS IN OUR BREASTS

ZARATE, L; PONTILLO, CAROLINA; ALEJANDRO ESPAÑOL; MIRET NOELIA; CHIAPPINI FLORENCIA; COCCA CLAUDIA; ALVAREZ L; DE PISAREV DIANA KLEIMAN; MARÍA E. SALES; RANDI, ANDREA

Congreso; LXIII REUNION ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA; 2018

Breastcancer is the most frequent tumor in women worldwide. Pesticides that act asendocrine disruptors have been shown to affect normal mammary development. Inthis study, we examined the action of Hexachlorobenzene (HCB) and Chlorpyrifos(CPF) on angiogenesis inmammary carcinogenesis in vivo and in vitro. We analyzed the levels ofproangiogenic factors such as vascular endothelial growth factor (VEGF) andcyclooxygenase-2 (COX-2), as well as the expression of the nitric oxidesynthases (NOS) by WB and their production of nitric oxide (NO) by Griessreagent. In a xenograft model with MCF-7 cells (+ERα), HCB (3 mg/kg b.w.)and CPF (0.1 mg/kg b.w.) enhance angiogenic switch (number of vessels/mm2)and increase VEGF expression in mice skin (p<0.05). For in vitro time-course studies, HCB (0.005 µM) at 3 h increases VEGF,COX-2 and NOS protein levels (p<0.05), while 5 µM enhances VEGF and COX-2levels (p<0.001) at 24 h, but decreases NOS expression at different times. CPF(0.05 and 50 µM) at 6 and 24 h, increases all involved protein expression(p<0.05). Exposure to each pesticide enhances NO production (0.005 µM HCB at3 h and 0.05 µM CPF at 3 and 6 h; p<0.05). To demonstrate that VEGF andCOX-2 induction occurs through NO-dependent mechanism, we inhibited (L-NMMA) theproduction of NO in the presence of pesticides at low doses. We found thatL-NMMA prevents the increase in VEGF and COX-2 expression in MCF-7 induced byHCB or CPF (p<0.001). The environmentaldoses of HCB and CPF stimulate angiogenic switch and VEGF expression in vivo. Pesticides induce VEGF, COX-2 andNOS expression in MCF-7 at similar doses that promote proliferation andangiogenesis. These alterations could contribute to the formation ofpreneoplastic lesions in the healthy mammary gland, as well as to theprogression in human breast tumors.