ArticlePloS one2010
Aromatase is a direct target of FOXL2: C134W in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 141 citations in OpenAlex.
- Open-label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: the Greko II study (GETHI2013-01).Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Trial
- Basket study of oral progesterone antagonist onapristone extended-release in combination with anastrozole in progesterone receptor-positive recurrent adult-type granulosa cell tumor of the ovary.International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2025Trial
- Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Trial
- Ontogeny of RSPO1, FOXL2, and RUNX1 during ovarian differentiation in the marsupial tammar wallaby.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- Hyperandrogenism in polycystic ovary syndrome augments Estrogen synthesis through AR-FOXL2-mediated activation of the aromatase gene in granulosa cells.Journal of ovarian research · 2025Article
- FOXL2 drives the differentiation of supporting gonadal cells in early ovarian development.Reproductive biology and endocrinology : RB&E · 2025Article
- A cellular model provides insights into the pathogenicity of the oncogenic FOXL2 somatic variant p.Cys134Trp.British journal of cancer · 2024Article
- It's a trap?! Escape from an ancient, ancestral sex chromosome system and implication of Foxl2 as the putative primary sex-determining gene in a lizard (Anguimorpha; Shinisauridae).Evolution; international journal of organic evolution · 2024Article
- Article
- It's a Trap?! Escape from an ancient, ancestral sex chromosome system and implication ofbioRxiv : the preprint server for biology · 2023Article
- ERβ in Granulosa Cell Tumors and Its Clinical Potential.Endocrinology · 2023Review
- ATAC-seq and RNA-seq analysis unravel the mechanism of sex differentiation and infertility in sex reversal chicken.Epigenetics & chromatin · 2023Article
- Factors within the Developing Embryo and Ovarian Microenvironment That Influence Primordial Germ Cell Fate.Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation · 2023Review
- Transcriptome profiling of banana shrimp (Fenneropenaeus merguiensis) ovaries and testes: Insights into FoxL2.PloS one · 2023Article
- Sex blind: bridging the gap between drug exposure and sex-related gene expression inFrontiers in toxicology · 2023Article
- Avian Sex Determination: A Chicken and Egg Conundrum.Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation · 2023Review
- CYP19A1 Promoters Activity in Human Granulosa Cells: A Comparison between PCOS and Normal Subjects.Cell journal · 2022Article
- Identification of SF-1 andFrontiers in endocrinology · 2022Article
- Estrogen disorders: Interpreting the abnormal regulation of aromatase in granulosa cells (Review).International journal of molecular medicine · 2021Review
- FOXO1 mitigates the SMAD3/FOXL2Journal of translational medicine · 2021Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGranulosa cell tumors (GCT) of the ovary often express aromatase and synthesize estrogen, which in turn may influence their progression. Recently a specific point mutation (C134W) in the FOXL2 protein was identified in >94% of adult-type GCT and it is likely to contribute to their development. A number of genes are known to be regulated by FOXL2, including aromatase/CYP19A1, but it is unclear which are direct targets and whether the C134W mutation alters their regulation. Recently, it has been reported that FOXL2 forms a complex with steroidogenic factor 1 (SF-1) which is a known regulator of aromatase in granulosa cells. METHODOLOGY/PRINCIPAL
findingsIn this work, the human GCT-derived cell lines KGN and COV434 were heterozygous and wildtype for the FOXL2:C134W mutation, respectively. KGN had abundant FOXL2 mRNA expression but it was not expressed in COV434. Expression of exogenous FOXL2:C134W in COV434 cells induced higher expression of a luciferase reporter for the ovarian specific aromatase promoter, promoter II (PII) (-516bp) than expression of wildtype FOXL2, but did not alter induction of a similar reporter for the steroidogenic acute regulatory protein (StAR) promoter (-1300bp). Co-immunoprecipitation confirmed that FOXL2 bound SF-1 and that it also bound its homologue, liver receptor homologue 1 (LRH-1), however, the C134W mutation did not alter these interactions or induce a selective binding of the proteins. A highly conserved putative binding site for FOXL2 was identified in PII. FOXL2 was demonstrated to bind the site by electrophoretic mobility shift assays (EMSA) and site-directed mutagenesis of this element blocked its differential induction by wildtype FOXL2 and FOXL2:C134W. CONCLUSIONS/SIGNIFICANCE: These findings suggest that aromatase is a direct target of FOXL2:C134W in adult-type GCT via a single distinctive and highly conserved binding site in PII and therefore provide insight into the pathogenic mechanism of this mutation.
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