RRC ID 69776
Author Cluzet V, Devillers MM, Petit F, Pierre A, Giton F, Airaud E, L'Hôte D, Leary A, Genestie C, Treilleux I, Mayeur A, Katzenellenbogen JA, Kim SH, Cohen-Tannoudji J, Chauvin S, Guigon CJ.
Title Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα-dependent mechanism.
Journal J Pathol
Abstract Granulosa cell tumor (GCT) is a form of ovarian tumor characterized by its tendency to recur years after surgical ablation. Little is known about the mechanisms involved in GCT development and progression. GCTs can produce estradiol (E2), but whether this hormone could play a role in this cancer through its nuclear receptors, i.e. ERα and ERβ, remains unknown. Here, we addressed this issue by cell-based and molecular studies on human GCTs and GCT cell lines. Importantly, we observed that E2 significantly increased the growth of GCT cells by promoting cell survival. The use of selective agonists of each type of receptor, together with Esr1 (ERα) or Esr2 (ERβ)-deleted GCT cells, revealed that E2 mediated its effects through ERα-dependent genomic mechanisms and ERβ/ERα-dependent extra-nuclear mechanisms. Notably, the expression of Greb1, a prototypical ER target gene, was dose-dependently upregulated by E2 specifically through ERα in GCT cells. Accordingly, using GCTs from patients, we found that GREB1 mRNA abundance was positively correlated to intra-tumoral E2 concentrations. Tissue microarray analyses showed that there were various combinations of ER expression in primary and recurrent GCTs, and that ERα expression persisted only in combination with ERβ in ~40% of recurrent tumors. Altogether, this study demonstrates that E2 can promote the progression of GCTs, with a clear dependence on ERα. In addition to demonstrating that GCTs can be classified as a hormone-related cancer, our results also highlight that the nature of ER forms present in recurrent GCTs could underlie the variable efficiency of endocrine therapies. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Volume 256(3)
Pages 335-348
Published 2022-3-1
DOI 10.1002/path.5843
PMID 34860414
MeSH Aged Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Estradiol / pharmacology* Estrogen Receptor alpha / agonists* Estrogen Receptor alpha / genetics Estrogen Receptor alpha / metabolism Estrogen Receptor beta / agonists Estrogen Receptor beta / genetics Estrogen Receptor beta / metabolism Female Gene Expression Regulation, Neoplastic Granulosa Cell Tumor / genetics Granulosa Cell Tumor / metabolism* Granulosa Cell Tumor / pathology Humans Middle Aged Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Ovarian Neoplasms / genetics Ovarian Neoplasms / metabolism* Ovarian Neoplasms / pathology Receptors, Estrogen / genetics Receptors, Estrogen / metabolism Receptors, G-Protein-Coupled / agonists Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / metabolism Signal Transduction Up-Regulation
IF 6.021
Human and Animal Cells KGN(RCB1154)