Alterations in c-Src/HER1 and Estrogen Receptor alfa signaling pathways in mammary gland and tumors of Hexachlorobenzene-treated rats.

DELFINA PEÑA; CAROLINA PONTILLO; MARIA ALEJANDRA GARCÍA; CLAUDIA COCCA; LAURA ALVAREZ; FLORENCIA CHIAPPINI; NADIA BOURGUIGNON; ISABEL FRAHM; ROSA BERGOC; DIANA KLEIMAN DE PISAREV; ANDREA RANDI

TOXICOLOGY

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2012 vol. 293 p. 68 - 77

0300-483X

Hexachlorobenzene (HCB) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents. The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors. We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells, in an estrogen receptor alfa (ERalfa)-dependent manner, and of migration in MDA-MB-231 breast cancer cell line. In the present study, we examined HCB effect on c-Src/human epidermal growth factor receptor (HER1) and ERalfa signaling pathways in mammary glands and in N-nitroso-N-methylurea (NMU)-induced mammary tumors in rats. Furthermore, we evaluated histopathological changes and serum hormone levels. Rats were separated into four groups: control, HCB (100 mg/kg b.w.), NMU (50 mg/kg b.w.) and NMU-HCB. Our data show that HCB increases c-Src and HER1 activation, c-Src/HER1 association, and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands. HCB also enhances Y537-ERalfa phosphorylation and ERalfa/c-Src physical interaction. In tumors, HCB also induces c-Src and HER1 activation, c-Src/HER1 association, as well as T308-Akt and Y699-STAT5b phosphorylation. In addition, the pesticide increases ERalfa protein content and decreases p-Y537-ERalfa levels and ERalfa/c-Src association in tumors. HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone, FSH and LH levels in rats without tumors, while the opposite effect was observed in rats with tumors. Taken together, our results indicate that HCB induces an estrogenic effect in mammary gland, increasing c-Src/HER1 and ERalfa signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ERalfa activity in tumors, appearing to shift them towards a higher malignancy phenotype.