TOX high mobility group box family member 3, also known asTOX3, is a humangene.[1][2]
Theprotein encoded by this gene is a member of a subfamily oftranscription factors that also includesTOX,TOX2, andTOX4 that share almost identicalHMG-boxDNA-binding domains which function to modifychromatin structure by unwinding and bending DNA.[3] The protein TOX3 has a glutamine-rich C-terminus due to CAG repeats.[4]TOX3 is located on human chromosome band 16q12.1.[5] The gene consists of seven exons and is highly expressed in both the brain and luminal epithelial breast tissue.[6] Mutations in the gene are associated with increased susceptibility to breast cancer.[2]TOX3 plays a role in regulating calcium-dependent transcription and interacts with cAMP-response-element-binding protein (CREB) and CREB-binding protein (CBP).[7] It also increases transcription via interaction withCITED1, a transcription co-regulator that increases transcription factor activity.[7]
The risk allele rs3803662 is a low-penetranceSNP (single nucleotide polymorphism) associated with decreased expression ofTOX3 and an increase in breast cancer risk.[7] The risk locus was reported to regulate affinity ofFOXA1 binding to chromatin, potentially affectingTOX3 expression.[6] This locus also interacts with high-penetrance mutationsBRCA1 andBRCA2 to increase risk.[10] The rs3803662 variant has a high frequency in the population, with a minor allele frequency of 0.25.[11]
Little is known of the transcriptional mechanisms and protein interactions ofTOX3. However, a 2019 publication identifiedTOX3 as a cancer suppressor gene inclear cell renal cell carcinoma (ccRCC) and reported that downregulation ofTOX3 facilitates theepithelial mesenchymal transition by decreasing repression ofSNAI1 andSNAI2, resulting in tumor growth and metastasis.[12] Like breast cancer, downregulation ofTOX3 is associated with worse prognosis in ccRCC patients.[12]
^abSmid M, Wang Y, Klijn JG, Sieuwerts AM, Zhang Y, Atkins D, et al. (May 2006). "Genes associated with breast cancer metastatic to bone".Journal of Clinical Oncology.24 (15):2261–7.doi:10.1200/JCO.2005.03.8802.PMID16636340.
^Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, et al. (July 2007). "Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer".Nature Genetics.39 (7):865–9.doi:10.1038/ng2064.PMID17529974.S2CID7346190.
^abJiang B, Chen W, Qin H, Diao W, Li B, Cao W, et al. (May 2019). "TOX3 inhibits cancer cell migration and invasion via transcriptional regulation of SNAI1 and SNAI2 in clear cell renal cell carcinoma".Cancer Letters.449:76–86.doi:10.1016/j.canlet.2019.02.020.PMID30772441.S2CID73487599.
