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 17β-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 ERα 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.
Footnotes
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This research was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Università e Ricerca Scientifica e Tecnologica, the Regione Calabria and Swiss National Science Foundation, Krebsforschung Schweiz, and the Canton the Genève (to D.P.).
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ABBREVIATIONS: TC, thyroid carcinoma; GPR30, G protein couplet receptor 30; G, genistein; OHT, 4-hydroxytamoxifen; DEX, dexamethasone; PRG, progesterone; PR, progesterone receptor; PD 98059 and PD, 2′-amino-3′-methoxyflavone; ER, estrogen receptor; E2, 17β-estradiol; ERE, estrogen response element; MAPK, mitogen-activated protein kinase; AF, activation function; GPCR, G protein-coupled receptor; Cx, cycloheximide; WM, wortmannin; PT, pertussis toxin; DHT, 5α-dihydrotestosterone; ICI 182,780 and ICI, faslodex; AG 1478, 4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline; AG 490, α-cyano-(3,4-dihydroxy)-N-benzylcinnamide; H-89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4,d]pyrimidine; FBS, fetal bovine serum; PCR, polymerase chain reaction; RT-PCR, reverse-transcriptase polymerase chain reaction; bp, base pair(s); kb, kilobase(s); ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphoinositide-3 kinase; EGFR, epidermal growth factor receptor; AP-1, activator protein 1; JAK, Janus tyrosine kinase; AS-ODN, antisense oligodeoxynucleotide; LY 294,002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one.
- Received May 5, 2006.
- Accepted July 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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