TY - JOUR
T1 - Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα-dependent mechanism
AU - Cluzet, Victoria
AU - Devillers, Marie M.
AU - Petit, Florence
AU - Pierre, Alice
AU - Giton, Frank
AU - Airaud, Eloïse
AU - L'Hôte, David
AU - Leary, Alexandra
AU - Genestie, Catherine
AU - Treilleux, Isabelle
AU - Mayeur, Anne
AU - Katzenellenbogen, John A.
AU - Kim, Sung Hoon
AU - Cohen-Tannoudji, Joëlle
AU - Chauvin, Stéphanie
AU - Guigon, Céline J.
N1 - Publisher Copyright:
© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - FOXL2
KW - GPER
KW - GREB1
KW - estradiol
KW - estrogen receptor
KW - granulosa cell tumor
KW - ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=85122217936&partnerID=8YFLogxK
U2 - 10.1002/path.5843
DO - 10.1002/path.5843
M3 - Article
C2 - 34860414
AN - SCOPUS:85122217936
SN - 0022-3417
VL - 256
SP - 335
EP - 348
JO - Journal of Pathology
JF - Journal of Pathology
IS - 3
ER -