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
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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.
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Recent in vitro studies confirm growth-promoting effects of estrogen on the ACC cell line NCI-H295.
“Interestingly, recent in vitro studies confirm growth-promoting effects of estrogen on the ACC cell line NCI-H295 (20).”
From Adrenocortical carcinoma (2014) · cites this paper as [20]
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- Authors
- Sirianni, R., Zolea, F., Chimento, A., Ruggiero, C., Cerquetti, L., Fallo, F., Pilon, C., Arnaldi, G., Carpinelli, G., Stigliano, A., & Pezzi, V.
- Affiliations
- University of Calabria (IT)
- Azienda Ospedaliera Sant'Andrea (IT)
- University of Padua (IT)
- Division of Endocrinology (G.A.), University of Ancona, 60020 Ancona, Italy;
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Sirianni, Rosa
- Pezzi, Vincenzo
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-12-01
- Volume
- 97
- Issue
- 12
- Pages
- E2238-E2250
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2088465409
- Cited by
- 58
- References
- 60
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 2 · 2013: 6 · 2012: 1
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
- IRIS UniPA (University of Palermo) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- adrenocortical carcinoma, estrogen receptor alpha, selective estrogen receptor modulators, tamoxifen, insulin-like growth factor II, estradiol, IGF-1 receptor, steroidogenic factor 1, aromatase, cyclin D1, non-genomic estrogen signaling, ERK1/2, Akt, CREB, H295R cells, tumor cell proliferation, tumor xenografts
- MeSH terms
- Adrenal Cortex Neoplasms, Animals, Carcinoma, Female, Humans, Mice, Nude, Down-Regulation, Gene Expression Regulation, Neoplastic, Antineoplastic Agents, Hormonal, Selective Estrogen Receptor Modulators, Xenograft Model Antitumor Assays, Cell Line, Tumor, Estrogen Receptor alpha, Cell Proliferation, Mice, Molecular Targeted Therapy
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