Dataset Information

17?-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.

SUBMITTER: Francois CM

PROVIDER: S-EPMC4417342 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.

François Charlotte M CM Wargnier Richard R Petit Florence F Goulvent Thibaut T Rimokh Ruth R Treilleux Isabelle I Ray-Coquard Isabelle I Zazzu Valeria V Cohen-Tannoudji Joëlle J Guigon Céline J CJ

Carcinogenesis 20150330 5

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 incr ...[more]

PMID: 25823895

Similar Datasets

Project description:Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Dataset Information

17?-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.

Publications

17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets