title: In vivo treatments with fulvestrant and anastrozole differentially affect gene expression in the rat efferent ductules.
abstract: Estrogen plays a key role in maintaining the morphology and function of the efferent ductules. We previously demonstrated that the antiestrogen fulvestrant markedly affected gene expression in the rat efferent ductules. The mechanism of fulvestrant action to modulate gene expression may involve not only the blockade of ESR1 and ESR2 estrogen receptors, but also the activation of ESR1 and ESR2 when the receptors are tethered to AP-1 or SP1 transcription factors, or the activation of the G protein-coupled estrogen receptor 1. We therefore compared the effects of two strategies to interfere with estrogen action in the rat efferent ductules: treatment with fulvestrant or with the aromatase inhibitor anastrozole. Whereas fulvestrant markedly increased Mmp7 and Spp1, and reduced Nptx1 mRNA levels, no changes were observed with anastrozole. Fulvestrant caused changes in epithelial morphology that were not seen with anastrozole. Fulvestrant shifted MMP7 immunolocalization in the epithelial cells from the supranuclear to the apical region; this effect was less pronounced with anastrozole. In vitro studies of (35)S-methionine incorporation showed that protein release was increased, whereas tissue protein content in the efferent ductules of fulvestrant-treated rats was decreased. Although fulvestrant markedly affected gene expression, no changes were observed on AP-1 and SP1 DNA-binding activity. The blockade of ESRs seems to be the major reason explaining the differences between both treatments. At least some of the effects of fulvestrant appear to result from compensatory mechanisms activated by the dramatic changes caused by ESR1 blockade.
authors.affiliation: Section of Experimental Endocrinology, Department of Pharmacology, Universidade Federal de São Paulo, Instituto Nacional de Farmacologia e Biologia Molecular, Vila Clementino, São Paulo, Brazil.
authors.forename: Gisele Renata Oliveira
authors.initials: GR
authors.lastname: Gomes
authors.forename: Fabiana
authors.initials: F
authors.lastname: Yasuhara
authors.forename: Erica Rosanna
authors.initials: ER
authors.lastname: Siu
authors.forename: Sheilla Alessandra Ferreira
authors.initials: SA
authors.lastname: Fernandes
authors.forename: Maria Christina Werneck
authors.initials: MC
authors.lastname: Avellar
authors.forename: Maria Fatima Magalhaes
authors.initials: MF
authors.lastname: Lazari
authors.forename: Catarina Segreti
authors.initials: CS
authors.lastname: Porto
mesh_terms: D000077384:Anastrozole; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D004543:Ejaculatory Ducts / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D013739:Testosterone; D004958:Estradiol