Journal
JOURNAL OF PATHOLOGY
Volume 256, Issue 3, Pages 335-348Publisher
WILEY
DOI: 10.1002/path.5843
Keywords
ovarian cancer; estradiol; estrogen receptor; GPER; GREB1; granulosa cell tumor; FOXL2
Funding
- Fondation Association pour la Recherche contre le Cancer
- Gefluc Ile-de-France
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- Center National de la Recherche Scientifique (CNRS)
- Universite de Paris
- Ecole Doctorale Bio-SPC
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This study demonstrates that estrogen (E2) can promote the progression of granulosa cell tumors (GCTs) by regulating ER alpha, and GCTs can be classified as hormone-related cancer. Moreover, the different forms of ER present in recurrent GCTs may underlie the variable efficiency of endocrine therapies.
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. ER alpha and ER beta, 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 (ER alpha) or Esr2 (ER beta)-deleted GCT cells, revealed that E2 mediated its effects through ER alpha-dependent genomic mechanisms and ER beta/ER alpha-dependent extra-nuclear mechanisms. Notably, the expression of Greb1, a prototypical ER target gene, was dose-dependently upregulated by E2 specifically through ER alpha 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 ER alpha expression persisted only in combination with ER beta in similar to 40% of recurrent tumors. Altogether, this study demonstrates that E2 can promote the progression of GCTs, with a clear dependence on ER alpha. 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. (C) 2022 The Pathological Society of Great Britain and Ireland.
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