Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
Department of Pharmaco-Biology Edificio Polifunzionale, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
Rosa
R
Sirianni
Fabiana
F
Zolea
Adele
A
Chimento
Carmen
C
Ruggiero
Lidia
L
Cerquetti
Francesco
F
Fallo
Catia
C
Pilon
Giorgio
G
Arnaldi
Giulia
G
Carpinelli
Antonio
A
Stigliano
Vincenzo
V
Pezzi
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators