TOX3

TOX high mobility group box family member 3
Identifiers
Symbol	TOX3
Alt. symbols	TNRC9, CAGF9
NCBI gene	27324
HGNC	11972
OMIM	611416
RefSeq	XM_049037
UniProt	O15405
Other data
Locus	Chr. 16 q12.1
Search for Structures Swiss-model Domains InterPro

TOX high mobility group box family member 3, also known as TOX3, is a human gene.^[1][2]

The protein encoded by this gene is a member of a subfamily of transcription factors that also includes TOX, TOX2, and TOX4 that share almost identical HMG-box DNA-binding domains which function to modify chromatin 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 with CITED1, a transcription co-regulator that increases transcription factor activity.^[7]

Disease linkage

Mutations in the TOX3 gene are associated with an increased risk of breast cancer.^[1][2][8][9]

The risk allele rs3803662 is a low-penetrance SNP (single nucleotide polymorphism) associated with decreased expression of TOX3 and an increase in breast cancer risk.^[7] The risk locus was reported to regulate affinity of FOXA1 binding to chromatin, potentially affecting TOX3 expression.^[6] This locus also interacts with high-penetrance mutations BRCA1 and BRCA2 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 of TOX3. However, a 2019 publication identified TOX3 as a cancer suppressor gene in clear cell renal cell carcinoma (ccRCC) and reported that downregulation of TOX3 facilitates the epithelial mesenchymal transition by decreasing repression of SNAI1 and SNAI2, resulting in tumor growth and metastasis.^[12] Like breast cancer, downregulation of TOX3 is associated with worse prognosis in ccRCC patients.^[12]

References

1. Smid 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. PMID 16636340.
2. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. (June 2007). "Genome-wide association study identifies novel breast cancer susceptibility loci". Nature. 447 (7148): 1087–93. Bibcode:2007Natur.447.1087E. doi:10.1038/nature05887. PMC 2714974. PMID 17529967.
3. O'Flaherty E, Kaye J (April 2003). "TOX defines a conserved subfamily of HMG-box proteins". BMC Genomics. 4 (1): 13. doi:10.1186/1471-2164-4-13. PMC 155677. PMID 12697058.
4. "TOX3 TOX high mobility group box family member 3 [Homo sapiens (human)]". Gene - NCBI. National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine.
5. "TOX3 (TOX high mobility group box family member 3)". Atlas of Genetics and Cytogenetics in Oncology and Haematology.
6. Jones JO, Chin SF, Wong-Taylor LA, Leaford D, Ponder BA, Caldas C, Maia AT (2013). "TOX3 mutations in breast cancer". PLOS ONE. 8 (9): e74102. Bibcode:2013PLoSO...874102J. doi:10.1371/journal.pone.0074102. PMC 3777980. PMID 24069272.
7. Gudmundsdottir ET, Barkardottir RB, Arason A, Gunnarsson H, Amundadottir LT, Agnarsson BA, et al. (December 2012). "The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients". BMC Cancer. 12: 621. doi:10.1186/1471-2407-12-621. PMC 3553017. PMID 23270421.
8. 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. PMID 17529974. S2CID 7346190.
9. Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, et al. (April 2008). "Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers". American Journal of Human Genetics. 82 (4): 937–48. doi:10.1016/j.ajhg.2008.02.008. PMC 2427217. PMID 18355772.
10. "OMIM Entry - * 611416 - TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 3; TOX3". Online Mendelian Inheritance in Man (OMIM).
11. Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M (June 2010). "Genetic susceptibility to breast cancer". Molecular Oncology. 4 (3): 174–91. doi:10.1016/j.molonc.2010.04.011. PMC 5527934. PMID 20542480.
12. Jiang 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. PMID 30772441. S2CID 73487599.