Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα-dependent mechanism.
Aged
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Estradiol
/ pharmacology
Estrogen Receptor alpha
/ agonists
Estrogen Receptor beta
/ agonists
Female
Gene Expression Regulation, Neoplastic
Granulosa Cell Tumor
/ genetics
Humans
Middle Aged
Neoplasm Proteins
/ genetics
Ovarian Neoplasms
/ genetics
Receptors, Estrogen
/ genetics
Receptors, G-Protein-Coupled
/ agonists
Signal Transduction
Up-Regulation
FOXL2
GPER
GREB1
estradiol
estrogen receptor
granulosa cell tumor
ovarian cancer
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
10
11
2021
received:
27
05
2021
accepted:
30
11
2021
pubmed:
4
12
2021
medline:
1
3
2022
entrez:
3
12
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
ESR1 protein, human
0
ESR2 protein, human
0
Estrogen Receptor alpha
0
Estrogen Receptor beta
0
GPER1 protein, human
0
GREB1 protein, human
0
Neoplasm Proteins
0
Receptors, Estrogen
0
Receptors, G-Protein-Coupled
0
Estradiol
4TI98Z838E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-348Informations de copyright
© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Références
Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003; 21: 1180-1189.
Pectasides D, Pectasides E, Psyrri A. Granulosa cell tumor of the ovary. Cancer Treat Rev 2008; 34: 1-12.
Miller K, McCluggage WG. Prognostic factors in ovarian adult granulosa cell tumour. J Clin Pathol 2008; 61: 881-884.
Färkkilä A, Haltia UM, Tapper J, et al. Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary. Ann Med 2017; 49: 435-447.
Rey RA, Lhommé C, Marcillac I, et al. Antimüllerian hormone as a serum marker of granulosa cell tumors of the ovary: comparative study with serum alpha-inhibin and estradiol. Am J Obstet Gynecol 1996; 174: 958-965.
Lappöhn RE, Burger HG, Bouma J, et al. Inhibin as a marker for granulosa-cell tumors. N Engl J Med 1989; 321: 790-793.
Hutton SM, Webster LR, Nielsen S, et al. Immunohistochemical expression and prognostic significance of oestrogen receptor-alpha, oestrogen receptor-beta, and progesterone receptor in stage 1 adult-type granulosa cell tumour of the ovary. Pathology 2012; 44: 611-616.
Ciucci A, Ferrandina G, Mascilini F, et al. Estrogen receptor β: potential target for therapy in adult granulosa cell tumors? Gynecol Oncol 2018; 150: 158-165.
Chu S, Mamers P, Burger HG, et al. Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors. J Clin Endocrinol Metab 2000; 85: 1200-1205.
Chu S, Nishi Y, Yanase T, et al. Transrepression of estrogen receptor beta signaling by nuclear factor-κB in ovarian granulosa cells. Mol Endocrinol 2004; 18: 1919-1928.
Karnezis AN, Chen SY, Chow C, et al. Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines. Gynecol Oncol 2021; 160: 568-578.
Haltia UM, Pihlajoki M, Andersson N, et al. Functional profiling of FSH and estradiol in ovarian granulosa cell tumors. J Endocr Soc 2020; 4: bvaa034.
van Meurs HS, van der Velden J, Buist MR, et al. Evaluation of response to hormone therapy in patients with measurable adult granulosa cell tumors of the ovary. Acta Obstet Gynecol Scand 2015; 94: 1269-1275.
Lamm W, Schiefer A, Nöbauer IM, et al. Aromatase inhibitor therapy as effective rescue in a patient with tamoxifen-refractory metastatic granulosa cell tumor of the ovary. J Clin Oncol 2016; 34: e31-e33.
Jia M, Dahlman-Wright K, Gustafsson JÅ. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab 2015; 29: 557-568.
Hamilton KJ, Arao Y, Korach KS. Estrogen hormone physiology: reproductive findings from estrogen receptor mutant mice. Reprod Biol 2014; 14: 3-8.
François CM, Wargnier R, Petit F, et al. 17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1. Carcinogenesis 2015; 36: 564-573.
Rae JM, Johnson MD, Scheys JO, et al. GREB1 is a critical regulator of hormone dependent breast cancer growth. Breast Cancer Res Treat 2005; 92: 141-149.
Hodgkinson K, Forrest LA, Vuong N, et al. GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer. Oncogene 2018; 37: 5873-5886.
Ghosh MG, Thompson DA, Weigel RJ. PDZK1 and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer. Cancer Res 2000; 60: 6367-6375.
Laviolette LA, Hodgkinson KM, Minhas N, et al. 17β-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo. Int J Cancer 2014; 135: 1072-1084.
Andersson S, Sundberg M, Pristovsek N, et al. Insufficient antibody validation challenges oestrogen receptor beta research. Nat Commun 2017; 8: 15840.
Dutertre M, Gouédard L, Xavier F, et al. Ovarian granulosa cell tumors express a functional membrane receptor for anti-Müllerian hormone in transgenic mice. Endocrinology 2001; 142: 4040-4046.
Nishi Y, Yanase T, Mu Y, et al. Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology 2001; 142: 437-445.
Pierre A, Taieb J, Giton F, et al. Dysregulation of the anti-Müllerian hormone system by steroids in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2017; 102: 3970-3978.
Shah SP, Köbel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009; 360: 2719-2729.
Cluzet V, Devillers MM, Petit F, et al. Aberrant granulosa cell-fate related to inactivated p53/Rb signaling contributes to granulosa cell tumors and to FOXL2 downregulation in the mouse ovary. Oncogene 2020; 39: 1875-1890.
Devillers MM, Petit F, Cluzet V, et al. FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice. J Endocrinol 2019; 240: 215-228.
Anttonen M, Färkkilä A, Tauriala H, et al. Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis. Lab Invest 2011; 91: 1605-1614.
Dong L, Wang H, Su Z, et al. Steroidogenic acute regulatory protein is a useful marker for Leydig cells and sex-cord stromal tumors. Appl Immunohistochem Mol Morphol 2011; 19: 226-232.
Stauffer SR, Coletta CJ, Tedesco R, et al. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-α-selective agonists. J Med Chem 2000; 43: 4934-4947.
Meyers MJ, Sun J, Carlson KE, et al. Estrogen receptor-β potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 2001; 44: 4230-4251.
Bologa CG, Revankar CM, Young SM, et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2006; 2: 207-212.
Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 1997; 277: 1508-1510.
Inaoka Y, Yazawa T, Uesaka M, et al. Regulation of NGFI-B/Nur77 gene expression in the rat ovary and in Leydig tumor cells MA-10. Mol Reprod Dev 2008; 75: 931-939.
Banerjee SN, Tang M, O’Connell R, et al. PARAGON: a phase 2 study of anastrozole (An) in patients with estrogen receptor (ER) and / progesterone receptor (PR) positive recurrent/metastatic granulosa cell tumors/sex-cord stromal tumors (GCT) of the ovary. J Clin Oncol 2018; 36: 5524-5524.
Farinola MA, Gown AM, Judson K, et al. Estrogen receptor α and progesterone receptor expression in ovarian adult granulosa cell tumors and Sertoli-Leydig cell tumors. Int J Gynecol Pathol 2007; 26: 375-382.
Kim SY, Weiss J, Tong M, et al. Foxl2, a forkhead transcription factor, modulates nonclassical activity of the estrogen receptor-α. Endocrinology 2009; 150: 5085-5093.
Fleming NI, Knower KC, Lazarus KA, et al. Aromatase is a direct target of FOXL2: C134W in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter. PLoS One 2010; 5: e14389.
Georges A, L'Hôte D, Todeschini AL, et al. The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells. Elife 2014; 3: e04207.
Mueller SO, Katzenellenbogen JA, Korach KS. Endogenous estrogen receptor β is transcriptionally active in primary ovarian cells from estrogen receptor knockout mice. Steroids 2004; 69: 681-686.
Cheng M, Michalski S, Kommagani R. Role for growth regulation by estrogen in breast cancer 1 (GREB1) in hormone-dependent cancers. Int J Mol Sci 2018; 19: 2543.
Hale GE, Burger HG. Hormonal changes and biomarkers in late reproductive age, menopausal transition and menopause. Best Pract Res Clin Obstet Gynaecol 2009; 23: 7-23.
Drummond AE, Fuller PJ. The importance of ERbeta signalling in the ovary. J Endocrinol 2010; 205: 15-23.
Miki Y, Abe K, Suzuki S, et al. Suppression of estrogen actions in human lung cancer. Mol Cell Endocrinol 2011; 340: 168-174.
Chantalat E, Valera MC, Vaysse C, et al. Estrogen receptors and endometriosis. Int J Mol Sci 2020; 21: 2815.
Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 2005; 19: 1951-1959.
Pedram A, Razandi M, Wallace DC, et al. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 2006; 17: 2125-2137.