title: 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30.
abstract: The higher incidence of thyroid carcinoma (TC) in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogens have suggested a pathogenetic role exerted by these steroids in the development of TC. In the present study, we evaluated the potential of 17beta-estradiol (E2), genistein (G), and 4-hydroxyta-moxifen (OHT) to regulate the expression of diverse estrogen target genes and the proliferation of human WRO, FRO, and ARO thyroid carcinoma cells, which were used as a model system. We have ascertained that ARO cells are devoid of estrogen receptors (ERs), whereas both WRO and FRO cells express a single variant of ERalpha that was neither transactivated, modulated, nor translocated into the nucleus upon treatment with ligands. However, E2, G, and OHT were able either to induce the transcriptional activity of c-fos promoter constructs, including those lacking the estrogen-responsive elements, or to increase c-fos, cyclin A, and D1 expression. It is noteworthy that we have demonstrated that the G protein-coupled receptor 30 (GPR30) and the mitogen-activated protein kinase (MAPK) pathway mediate both the up-regulation of c-fos and the growth response to E2, G, and OHT in TC cells studied, because these stimulatory effects were prevented by silencing GPR30 and using the MEK inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Our findings provide new insight into the molecular mechanisms through which estrogens may induce the progression of TC.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, 87030 Rende (CS), Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Lidia
authors.initials: L
authors.lastname: Albanito
authors.forename: Antonio
authors.initials: A
authors.lastname: Madeo
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rago
authors.forename: Amalia
authors.initials: A
authors.lastname: Carpino
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Musti
authors.forename: Didier
authors.initials: D
authors.lastname: Picard
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; C109584:GPER1 protein, human; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; D019938:Cyclin D1; C016601:afimoxifene; D004958:Estradiol; D019833:Genistein