TOX3 and the risk of breast cancer; an overview

Background and Review of the literatureBreast cancer is the most common cause ofmalignancy and cancer mortality among women globally. Both environmental and geneticfactors are involving in the risk of breast cancer. Genetic risk factors such as variations inTOX3 which contribute to the liability, play an important role in development of the disease.Genome wide association studies (GWAs) have demonstrated high frequency but lowpenetrance disease-associated single nucleotide polymorphisms (SNP) in TOX3 gene. Thisgene encodes the HMG-box nuclear protein TOX high mobility group box family member 3(TOX3). TOX3 (TNRC9), is a non-histone chromatin protein including a nuclear localizationsignal and a HMG-box domain followed by a C-terminal polyglutamine stretch. It has calciumdependenttranscriptional activity and is a co-factor of cAMP response element (CRE)-binding protein (CREB) and CREB-binding protein (CBP). Calcium mediates TOX3 induced cfosexpression and activation of the c-fos promoter. TOX3 was shown to be expresseddownstream of a cytoprotective cascade together with CITED1, a transcriptional regulatorthat increases transcription mediated via diverse transcription factors, such as estrogenreceptors or early growth response 2. In addition, TOX3 over-expression protects neuronalcells from cell death due to BAX over-expression or endoplasmic reticulum stress during theinduction of anti-apoptotic transcripts and repression of pro-apoptotic transcripts. TOX3 canalso mediate cytoprotective transcription from the BCL-2 promoter or the complement C3promoter, depending on the predominance of either phosphorylated CREB or CITED1 withinthe transcriptionally active complex. TOX3 maps to chromosome 16q12 and consists ofseven exons. A SNP near its 5ʹ end and promoter of TOX3 gene appears to be stronglyassociated with breast cancer susceptibility. Furthermore, breast cancer†associated SNPsare enriched for FOXA1 that led to enhanced FOXA1 binding and a decrease in TOX3 geneexpression. Conclusion

کلیدواژه ها:

Breast cancer ، TOX3 ، CREB-Binding Protein ، FOXA1 protein ، BCL-2