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 DE PISAREV; ANDREA RANDI

Dresden, Alemania

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

Sociedades Europeas de Toxicología

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:1; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:variable; mso-font-signature:0 0 0 0 0 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:"Times New Roman";} p {mso-style-unhide:no; mso-margin-top-alt:auto; margin-right:0cm; mso-margin-bottom-alt:auto; margin-left:0cm; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt;} @page WordSection1 {size:595.3pt 841.9pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --> 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.