title: Action of hexachlorobenzene on tumor growth and metastasis in different experimental models.
abstract: Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR-dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5μM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30mg/kg b.w.) on tumor growth, MMP2 and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5μM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30mg/kg b.w.) activated c-Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression.
authors: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. caroponti@hotmail.com
authors: Carolina Andrea
authors: CA
authors: Pontillo
authors: Paola
authors: P
authors: Rojas
authors: Florencia
authors: F
authors: Chiappini
authors: Gonzalo
authors: G
authors: Sequeira
authors: Claudia
authors: C
authors: Cocca
authors: Máximo
authors: M
authors: Crocci
authors: Lucas
authors: L
authors: Colombo
authors: Claudia
authors: C
authors: Lanari
authors: Diana
authors: D
authors: Kleiman de Pisarev
authors: Andrea
authors: A
authors: Randi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D006581:Hexachlorobenzene / Q000633:toxicity*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D005659:Fungicides, Industrial; D006581:Hexachlorobenzene