Organochlorine pesticide triggers stimulation of c-Src dependent HER1-ERK 1/2 signaling pathway in mammary gland and N-methyl-N-nitrosourea (NMU)-induced mammary tumors in rats

DELFINA PEÑA; CAROLINA PONTILLO; MARÍA ALEJANDRA GARCÍA; CLAUDIA COCCA; LAURA ALVAREZ; ISABEL FRAHM, ; VICTORIA LUX-LANTOS, ; ROSA BERGOC; DIANA KLEIMAN DE PISAREV; Y ANDREA RANDI

Dresden

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

EUROTOX

Hexachlorobenzene (HCB) is one of the most widespread organochlorine environmental pollutants. Our previous studies show that HCB increases the number and malignancy of tumors in NMU-induced mammary tumors in rats. Evidence indicates that c-Src and HER1 synergize to enhance neoplastic growth of mammary epithelial cells. This interaction is dependent on c-Src-mediated phosphorylation of Y845-HER1, triggering proliferation, migration and metatasis. c-Src activates estrogen receptor α (ERα) via Y537 phosphorylation. Our aim was to study HCB mechanism of action in mammary gland (M) and NMU-induced mammary tumors (T) in rats on: a)HER1 levels and Y845-HER1 phosphorylation, b)c-Src activation, c)ERα levels and Y537-ERα phosphorylation, d)ERK1/2 activation and e)estrogen and progesterone serum levels. Study groups were: Control, HCB (100 mg/kg for 45 days), NMU (3 doses of 50 mg/kg) and NMU-HCB. Protein expression and phosphorylation were measured by immunoprecipitation and Western blot, and hormone levels by RIA. Results show that HCB: a)enhanced Y845-HER1 phosphorylation in M and T; b)increased c-Src protein levels in M and T, and decreased c-Src activation in T; c)raised citosolic and nuclear ERα levels in T; and enhanced Y537-ERα phosphorylation in M and decreased it in T; d)elicited ERK1/2 activation in M and decreased it in T, e)increased estrogen and decreased progesterone serum levels in HCB group, and conversely, decreased estrogen and increased progesterone serum levels in NMU-HCB treated rats. These results indicate that HCB induces c-Src dependent HER1 signaling pathway in mammary gland and tumors, which could explain the ductal hyperplasia and enhanced proliferation in mammary gland, and the increase in malignancy of tumors previously reported.