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Background  Women who undergo chronic exposure to excessive estrogen are at a high risk of developing breast cancer.  TOX3  has been reported to be highly expressed in breast tumors and is closely related to estrogen receptors. However, the effect of TOX3 on estrogen synthesis remains poorly understood.    Methods  Using lentiviruses as a vector, we stably overexpressed TOX3 in the ovarian granulosa cell line KGN, the cells where estradiol is primarily produced, to investigate its role in estrogen production as well as cell viability and apoptosis. RNA-Sequencing was applied to uncover the global gene expression upon TOX3 overexpression.    Results  We observed an increased level of cell viability and a reduced cell apoptosis rate after TOX3 overexpression, and the level of estradiol in the cell culture supernatant also increased significantly. Gene set enrichment analysis of the transcriptome showed that the ovarian steroidogenesis pathway was significantly enriched. Similarly, pathway mapping using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses also showed that TOX3 overexpression affects the ovarian steroidogenesis pathway. Further experiments showed that upregulated  FSHR ,  CYP19A1 , and  BMP6  accounted for the enhanced estrogen synthesis.    Conclusion  Our study demonstrated that TOX3 quantitatively and qualitatively stimulates estrogen synthesis by enhancing estrogen signaling pathway–related gene expression in ovarian granulosa cells. These findings suggest that TOX3 may play a vital role in the pathogenesis of breast cancer.

TOX3 Promotes Ovarian Estrogen Synthesis: An RNA-Sequencing and Network Study