Action of hexachlorobenzene on tumor growth and metastasis in different experimental models

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• 作者：Carolina Andrea Pontillo^a ; ^{caroponti@hotmail.com} ; Paola Rojas^b ; ^{parojas2010@gmail.com} ; Florencia Chiappini^a ; ^{florenciachiappini@hotmail.com} ; Gonzalo Sequeira^b ; ^{chicon27_7@hotmail.com} ; Claudia Cocca^c ; ^{cm_cocca@hotmail.com} ; Má ; ximo Crocci^d ; ^{info@crescenti.com.ar} ; Lucas Colombo^e ; ^{lucascol2003@yahoo.com.ar} ; Claudia Lanari^b ; ^{lanari.claudia@gmail.com} ; Diana Kleiman de Pisarev^a ; ^{dianakleiman@yahoo.com.ar} ; Andrea Randi^a ; ^{andybiol@yahoo.cm.ar}
• 关键词：Hexachlorobenzene ; MDA-MB-231 ; Cell invasion ; AhR ; MMPs ; Metastasis
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2013
• 出版时间：1 May, 2013
• 年：2013
• 卷：268
• 期：3
• 页码：331-342
• 全文大小：2196 K

文摘

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, 5 ¦ÌM) 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, 30 mg/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 (5 ¦ÌM) 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 3 mg/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 30 mg/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.