Abstract
Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22–73.04), ACC115m cells: 51.76 µM (95%CI: 46.45–57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18–5.69 µM) mainly involving ER-β, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: −36.34 ± 9.26%; tamoxifen: −46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency.
Highlights
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor with an incidence of 0.7–2 new cases per million populations per year [1]
Concerning the ACC cell lines, NCI-H295R cells expressed both estrogen receptors (ERs) subtypes, the gene and the protein both indicated a low level of expression with a prevalence of ER-b over the ER-a (Figure 1A, Supplemental Figures 1, 2)
Drug exposure led to an increased nuclear localization of ER-b subtype, with no modifications of the ER-a subcellular localization, leading to the hypothesis that the cytotoxic and antiproliferative effects of tamoxifen in ACC cells could be mediated by its ER-b agonist activity, according to previous observations [38]
Summary
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor with an incidence of 0.7–2 new cases per million populations per year [1]. Diagnosis followed by radical surgical resection associated or not with adjuvant mitotane therapy [2, 3] is the only option that can give to ACC patients a chance of cure [4]. The standard systemic treatment for advanced/metastatic ACC patients, not eligible to surgery, is mitotane, which is administered either alone or in combination with Etoposide, Doxorubicin, and Cisplatin (EDP-M regimen) [5]. Some pathological responses have been observed [6], the efficacy of EDP-M is limited and most initially responding patients are destined to relapse and die of the disease. Other cytotoxic therapies administered to patients with disease progression to EDP-M did not show a remarkable activity [7, 8]. Molecular target therapies, attempted up to now [9], and immunotherapy [10] appeared ineffective
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
