Context: Adrenocortical carcinoma (ACC) is a rare tumor with a very poor prognosis and no effective treatment.
ACC is characterized by an increased production of IGF-II and by estrogen receptor (ER)-α up-regulation.
Objective: The objective of this study was to define the role played by ERα in 17β-estradiol (E2)- and IGF-II-dependent ACC growth and evaluate whether selective estrogen receptor modulators are effective in controlling ACC growth in vivo. Experimental Design: The human adrenocortical cell line H295R was used as an in vitro model and to generate xenograft tumors in athymic nude mice.
Results: In H295R cells IGF-II controlled expression of steroidogenic factor-1 that, in turn, increased aromatase transcription and, consequently, estrogen production, inducing cell proliferation. ERα silencing significantly blocked E2- and IGF-II-dependent cell proliferation. This effect was dependent on the regulation of cyclin D1 expression by ERα, activated in response to both E2 and IGF-II. In fact, IGF-II induced ERα activation by phosphorylating serine 118 and 167. Furthermore, we demonstrated that ERα mediated E2-induced nongenomic signaling that stimulated IGF-I receptor (IGF1R), ERK1/2, and AKT phosphorylation, resulting in a ligand-independent activation of the IGF1R-induced pathway. In addition, E2 potentiated this pathway by up-regulating IGF1R expression as a consequence of increased cAMP-responsive element binding protein activation and binding to IGF1R promoter. The estrogen antagonist, hydroxytamoxifen, the active metabolite of tamoxifen, reduced IGF1R protein levels and both E2- and IGF-II-induced cell proliferation. Moreover, H295R xenograft growth was strongly reduced by tamoxifen.
Conclusion: These findings establish a critical role for ERα in E2- and IGF-II-dependent ACC proliferation and provide a rationale for targeting ERα to control the proliferation of ACC.
Written by:
Sirianni R, Zolea F, Chimento A, Ruggiero C, Cerquetti L, Fallo F, Pilon C, Arnaldi G, Carpinelli G, Stigliano A, Pezzi V. Are you the author?
Department of Pharmaco-Biology Edificio Polifunzionale, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
Reference: J Clin Endocrinol Metab. 2012 Dec;97(12):E2238-50.
doi: 10.1210/jc.2012-2374
PubMed Abstract
PMID: 23074235
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