Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors

• Published in: The international journal of biochemistry & cell biology 2016-03, Vol.72, p.51-54
• Main Authors: Leung, Dilys T.H., Fuller, Peter J., Chu, Simon
• Format: Article
• Language: English
• Subjects: Alterations; Animals; Biochemistry; Biology; Estrogens; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXL2; Genes; Granulosa cell tumor; Granulosa Cell Tumor - genetics; Granulosa Cell Tumor - pathology; Granulosa Cell Tumor - therapy; Humans; Mutation; Mutations; Ovarian cancer; Ovarian Follicle - growth & development; Ovary; Progressions; Tumors
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2016.01.003

•FOXL2 is the key player in granulosa cell differentiation and its expression is critical in maintaining ovarian phenotype.•Although more than 260 mutations identified in FOXL2 result in Blepharophimosis–Ptosis–Epicanthus inversus syndrome, only the FOXL2 C134W mutation is unique to granulosa cell tumors of the ovary.•Mutant FOXL2 has been found to alter hormone production, apoptotis and proliferation in vitro.•Further insights into FOXL2 signaling can be found at http://www.cancerindex.org/geneweb//FOXL2.htm. Granulosa cell tumors (GCT) are unique sex-cord stromal tumors which account for ∼8% of all ovarian malignancies. They exhibit morphological, biochemical and hormonal features similar to proliferating granulosa cells of the preovulatory follicle, including estrogen and inhibin synthesis. A somatic missense mutation in the forkhead box L2 (FOXL2) gene (C134W) is unique to adult GCT, and absent in other ovarian cancers. FOXL2 is a transcription factor that plays a critical role in ovarian function, in particular, proliferation and differentiation of granulosa cells. The molecular mechanisms underlying the pathogenicity of the mutant FOXL2 remain unresolved. Here we review the molecular alterations known to be associated with mutant FOXL2 and the potential signaling implications. Several studies suggest that dysregulated FOXL2 function may alter cell cycle progression and apoptosis. Further insights into the molecular mechanism of GCT pathophysiology may identify therapeutic targets for the treatment of these tumors.