Abstract
BackgroundWomen 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.MethodsUsing 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.ResultsWe 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.ConclusionOur 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.
Highlights
Breast cancer is one of the most commonly reported malignant tumors and a leading cause of death in women [1, 2]
We investigated the biological function of TOX3 in estrogen production in ovaries in order to further explain the relationship between TOX3 and breast cancer, using KGN cells, the most commonly used human granulosa cell line, which are capable of estrogen synthesis [17]
TOX3 has been recognized as a susceptible gene in breast cancer for many years, its molecular mechanism in the pathogenesis of breast cancer is still poorly understood
Summary
Breast cancer is one of the most commonly reported malignant tumors and a leading cause of death in women [1, 2]. The pathogenesis and development of breast cancer are associated with high levels of estrogen; it has been reported that 84% of breast cancers express estrogen and progesterone receptors, indicating the crucial role of the hormone in the development of breast cancer [3]. An increased level of endogenous estrogens was associated with a higher risk for breast cancer in women postmenopausal [6, 8]. For women throughout the reproductive years, estrogen exposure is likely to be associated with higher risk of breast cancer. 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. The effect of TOX3 on estrogen synthesis remains poorly understood
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