Hexachlorobenzene induces c-Src-HER1-ERK1/2 signaling pathway and stimulates migration in MDA-MB-231 breast cancer cell line

CAROLINA PONTILLO; DELFINA PEÑA; MARÍA ALEJANDRA GARCÍA; CLAUDIA COCCA; LAURA ALVAREZ; DIANA KLEIMAN; ANDREA RANDI

Dresden, Alemania

Congreso; 46th Congress of the European Societies of Toxicology EUROTOX 2009; 2009

Hexachlorobenzene (HCB) is a widespread environmental pollutant that triggers ?dioxin-like? effects. We have demonstrated that HCB administration to rats enhanced the development and malignancy of NMU-induced mammary tumors. c-Src-HER1 interactions contribute to tumor progression in certain late-stage breast tumor cells. c-Src-mediated phosphorylation of Y845-HER1 plays a role in triggering processes like proliferation and migration. Our aim was to study the effects of HCB on c-Src-HER1-ERK1/2 and AKT signaling pathways and cellular migration in ER-negative MDA-MB-231 cell line. Cells were grown in RPMI suplemented with 10% BFS, and were exposed to 0.005 ìM HCB for 5, 15, 30 min, 2 and 24 hours, and to HCB (0, 0.005, 0.05, 0.5 and 5 ìM) for 15 min. To measure migration, cells were exposed to HCB for 24 hours and scratch motility and transwell assays were made. Cellular lysates were analysed by immunoblot. Results: 1)Time-course assay: HCB induces phosphorylation in Y416-c-Src, Y845-HER1 and ERK1/2 at 5, 15 and 30 min; and in T308-AKT at 24 hours (0.05 ìM); 2)Dose-response assay (15 min): HCB increases phosphorylation in: a)Y416-c-Src at 0.005, 0.05 and 0.5 ìM; b)Y845-HER1 at 0.05 and 0.5 ìM; c)ERK1/2 at 0.05, 0.5 and 5 ìM; 3)Migration assay: HCB induces cell migration at 0.05 and 0.5 ìM in the scratch motility assay and at 5 ìM in the transwell method. In conclusion, our results demonstrate that HCB increases cell migration and induces c-Src-HER1-ERK1/2 and AKT signaling pathways in MDA-MB-231. This provides a clue to the molecular events involved in the mechanism of action of HCB in mammary cancer development.