Antiestrogens upregulate estrogen receptor β expression and inhibit adrenocortical H295R cell proliferation

D. Montanaro, M. Maggiolini, A. G. Recchia, R. Sirianni, S. Aquila, L. Barzon, F. Fallo, S. Andò, V. Pezzi

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


The molecular mechanisms involved in adrenocortical tumorigenesis are still not completely understood. In this study, using the H295R cell line as a model system, we investigated the role of estrogens and estrogen receptor (ER) α and ERβ in the growth regulation of adrenocortical tumors. We demonstrated that H295R cells are able to convert androgens to estrogens by a constitutive expression of active cytochrome P450 aromatase protein and express ERβ to a greater extent than ERα. Moreover, physiological concentrations of 17β-estradiol (E2) determined an increase of thymidine incorporation, suggesting the presence of an autocrine mechanism in maintaining H295R cell proliferation. Evaluating the response to ER antagonists like 4-hydroxytamoxifen (OHT) and ICI 182 780 (ICI), we observed an up-regulation of ERβ and a dose-dependent inhibition of H295R cell proliferation. Whereas ICI determined the growth arrest of H295R cells, OHT induced morphological changes that were characteristic of apoptosis. According to the above-mentioned observations, OHT but not ICI clearly induced a marked expression of FasL and the cleavage of both caspase-8 and caspase-3. Interestingly, the apoptotic effects of OHT in H295R cells may be consequent to the enhanced levels of ERβ which stimulate the expression of FasL interacting with activating protein (AP)-1 sites located within its promoter sequence. In conclusion, we have demonstrated that H295R cells are able to transform androgens to estrogens that activate an autocrine mechanism, mediated by their own receptors, and contribute to regulate the proliferation of these cells. Moreover, this study points towards a role for ERβ as an important mediator of the repressive effects exerted by antiestrogens on H295R cells; however, further studies are needed to clarify its role in the control of adrenocortical cell proliferation and on the potential benefits of antiestrogens for treatment of adrenocortical cancer.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
JournalJournal of molecular endocrinology
Issue number2
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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