title: Alterations in c-Src/HER1 and estrogen receptor α signaling pathways in mammary gland and tumors of hexachlorobenzene-treated rats.
abstract: 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 α (ERα)-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 ERα 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-ERα phosphorylation and ERα/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 ERα protein content and decreases p-Y537-ERα levels and ERα/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 ERα signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ERα activity in tumors, appearing to shift them towards a higher malignancy phenotype.
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Delfina
authors.initials: D
authors.lastname: Peña
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pontillo
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María Alejandra
authors.initials: MA
authors.lastname: García
authors.affiliation: Laboratorio de Radioisótopos, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocca
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Florencia
authors.initials: F
authors.lastname: Chiappini
authors.affiliation: Laboratorio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME, CONICET), Buenos Aires, Argentina.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bourguignon
authors.affiliation: Departamento de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina.
authors.forename: Isabel
authors.initials: I
authors.lastname: Frahm
authors.affiliation: Laboratorio de Radioisótopos, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bergoc
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Diana
authors.initials: D
authors.lastname: Kleiman de Pisarev
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: andybiol@yahoo.com.ar.
authors.forename: Andrea
authors.initials: A
authors.lastname: Randi
mesh_terms: D000818:Animals; D003043:Cocarcinogenesis; D052244:Endocrine Disruptors / Q000633:toxicity; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D006581:Hexachlorobenzene / Q000633:toxicity*; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D010908:Pituitary Hormones, Anterior / Q000097:blood; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D012739:Gonadal Steroid Hormones; D009363:Neoplasm Proteins; D010575:Pesticides; D010908:Pituitary Hormones, Anterior; D006581:Hexachlorobenzene; C512478:EGFR protein, human; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src)