title: 17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.
abstract: Granulosa cell tumor (GCT) is a rare and severe form of sex-cord stromal ovarian tumor that is characterized by its long natural history and tendency to recur years after surgical ablation. Because there is no efficient curative treatment beyond surgery, ~20% of patients die of the consequences of their tumor. However, very little is known of the molecular etiology of this pathology. About 70% of GCT patients present with elevated circulating estradiol (E2). Because this hormone is known to increase tumor growth and progression in a number of cancers, we investigated the possible role of E2 in GCTs. Cell-based studies with human GCT metastases and primary tumor-derived cells, ie KGN and COV434 cells, respectively, aimed at evaluating E2 effect on cell growth, migration and invasion. Importantly, we found that E2 did not affect GCT cell growth, but that it significantly decreased the migration and matrix invasion of metastatic GCT cells. Noteworthy, our molecular studies revealed that this effect was accompanied by the inhibition through non-genomic mechanisms of extracellular signal-regulated kinase 1/2 (ERK1/2), which is constitutively activated in GCTs. By using pharmacological and RNA silencing approaches, we found that E2 action was mediated by G protein-coupled estrogen receptor 1 (GPER1) signaling pathway. Analyses of GPER1 expression on tissue microarrays from human GCTs confirmed its expression in ~90% of GCTs. Overall, our study reveals that E2 would act via non-classical pathways to prevent metastasis spreading in GCTs and also reveals GPER1 as a possible target in this disease.
authors.affiliation: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, CNRS UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: François
authors.affiliation: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, CNRS UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Wargnier
authors.affiliation: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, CNRS UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.affiliation: U1052 INSERM, UMR CNRS 5286, Université de Lyon, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon F-69000, France, Institut Roche de Recherche et Médecine Translationnelle, 92650 Boulogne Billancourt, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Goulvent
authors.affiliation: U1052 INSERM, UMR CNRS 5286, Université de Lyon, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon F-69000, France.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.affiliation: Department of Pathology, Centre Léon Bérard, Lyon F-69000, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Université de Lyon, Lyon F-69000 and GINECO Group, Paris, France and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Institute of Genetics and Biophysics "A. Buzzati-Traverso"-CNR, I-80131 Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Zazzu
authors.affiliation: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, CNRS UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Cohen-Tannoudji
authors.affiliation: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, CNRS UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, celine.guigon@univ-paris-diderot.fr.
authors.forename: Céline J
authors.initials: CJ
authors.lastname: Guigon
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D004967:Estrogens; C109584:GPER1 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol
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