Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα‐dependent mechanism

• Published in: The Journal of pathology 2022-03, Vol.256 (3), p.335-348
• Main Authors: Cluzet, Victoria, Devillers, Marie M, Petit, Florence, Pierre, Alice, Giton, Frank, Airaud, Eloïse, L'Hôte, David, Leary, Alexandra, Genestie, Catherine, Treilleux, Isabelle, Mayeur, Anne, Katzenellenbogen, John A, Kim, Sung Hoon, Cohen‐Tannoudji, Joëlle, Chauvin, Stéphanie, Guigon, Céline J
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Aged; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; DNA microarrays; Endocrine therapy; ESR1 protein; estradiol; Estradiol - pharmacology; estrogen receptor; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - agonists; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Female; FOXL2; Gene Expression Regulation, Neoplastic; GPER; granulosa cell tumor; Granulosa Cell Tumor - genetics; Granulosa Cell Tumor - metabolism; Granulosa Cell Tumor - pathology; GREB1; Humans; Life Sciences; Middle Aged; mRNA; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear receptors; Ovarian cancer; 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; Tumors; Up-Regulation
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5843

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.