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

Rosa Sirianni, Fabiana Zolea, Adele Chimento, Carmen Ruggiero, Lidia Cerquetti, Francesco Fallo, Catia Pilon, Giorgio Arnaldi, Giulia Carpinelli, Antonio Stigliano, Vincenzo Pezzi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number12
DOIs
StatePublished - Dec 2012

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Adrenal Cortex Neoplasms
Selective Estrogen Receptor Modulators
Insulin-Like Growth Factor II
Oncology
Cell growth
Estrogen Receptors
Growth
Cell proliferation
Chemical activation
Cell Proliferation
Tamoxifen
Therapeutics
Heterografts
Nude Mice
Tumors
Steroidogenic Factor 1
IGF Type 2 Receptor
Adrenocortical Carcinoma
Estrogen Antagonists
IGF Type 1 Receptor

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Sirianni, Rosa; Zolea, Fabiana; Chimento, Adele; Ruggiero, Carmen; Cerquetti, Lidia; Fallo, Francesco; Pilon, Catia; Arnaldi, Giorgio; Carpinelli, Giulia; Stigliano, Antonio; Pezzi, Vincenzo.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 12, 12.2012.

Research output: Contribution to journalArticle

Sirianni, Rosa ; Zolea, Fabiana ; Chimento, Adele ; Ruggiero, Carmen ; Cerquetti, Lidia ; Fallo, Francesco ; Pilon, Catia ; Arnaldi, Giorgio ; Carpinelli, Giulia ; Stigliano, Antonio ; Pezzi, Vincenzo. / 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. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 12.
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abstract = "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.",
author = "Rosa Sirianni and Fabiana Zolea and Adele Chimento and Carmen Ruggiero and Lidia Cerquetti and Francesco Fallo and Catia Pilon and Giorgio Arnaldi and Giulia Carpinelli and Antonio Stigliano and Vincenzo Pezzi",
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T2 - Potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment

AU - Sirianni, Rosa

AU - Zolea, Fabiana

AU - Chimento, Adele

AU - Ruggiero, Carmen

AU - Cerquetti, Lidia

AU - Fallo, Francesco

AU - Pilon, Catia

AU - Arnaldi, Giorgio

AU - Carpinelli, Giulia

AU - Stigliano, Antonio

AU - Pezzi, Vincenzo

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