Association of rs4784227-CASC16 (LOC643714 locus) and rs4782447-ACSF3 polymorphisms and their association with breast cancer risk among Iranian population

TOX3 and FOXA1 proteins are believed to be involved in the susceptibility of breast cancer. rs4782447 and rs4784227, as single nucleotide polymorphisms (SNPs), located at the 16q may affect the FOXA1 DNA binding sequence change and therefore may enhance the FOXA1-binding affinity to the promoter of TOX3 gene. This study aimed to investigate the association of these SNPs/haplotypes with breast cancer susceptibility in Iranian population. We conducted a case-control study of 1072 blood samples (505 breast cancer patients and 567 controls). Genotyping of rs4784227 and rs4782447 SNPs was carried out by ARMS PCR. Moreover, statistical analysis was done by SPSS 20.0 (IBM Inc., Chicago, IL, USA) and SNP analyser 2.0. There was a strongly significant statistical association between alleles and genotypes of rs4784227 with breast cancer susceptibility in a group of Iranian women (p<0.05). Moreover, a significant association was demonstrated between TA haplotype and breast cancer risk (OR=0.78; 95% CI (0.62-0.96); P-value=0.025). In this respect, although we did not observe a statistically significant association between rs4782447 with breast cancer susceptibility, the combination of the alleles of rs4784227 and rs4782447 SNPs may also affect the risk. This is in line with other studies where they suggest these SNPs as risk-associated polymorphisms by which lead to disruption of as a distal enhancer, FOXA1, binding and following that change in TOX3 expression that can eventually affect the risk of breast cancer

TOX3 Gene polymorphisms and breast cancer; effects and implications of the variations: review article

Breast carcinoma is the most common cause of cancer mortality among women globally. Primary and secondary prevention through avoiding known risk factors, screening for early detection of tumors with different methods as well as timely treatment, can be effective in reduction of the burden of this devastating disease. This can in turn prevent death and also increase survival in patients with breast cancer. Both environmental and genetic factors are involved in the pathogenesis of breast cancer. Multiple genetic factors can influence the risk and development of breast cancer. Identification of genetic variants including single nucleotide polymorphisms (SNPs), which are associated with the risk of breast cancer development, are mostly done through genetic association studies. It is demonstrated that SNP allele frequencies vary amongst different populations. It has been shown that genetic risk factors like variations in TOX high mobility group box family member 3 (TOX3), which affect the liability for neoplasm, play an important role in the development of breast cancer. Although TOX3 is expressed mainly in the brain, its expression in other tissues especially breast has also been reported. TOX3 maps to chromosome 16q12 and encodes the nuclear high-mobility group (HMG)-box. It has calcium (Ca2+)-dependent transcriptional activities and is a co-factor of cAMP response element (CRE)-binding protein (CREB) and CREB-binding protein (CBP). TOX3, activated with Ca2+, is related with activation of the promoter of some other genes including BCL2 and C3 complement and also CITED1 gene expression. It also induces activation of the c-fos promoter and therefore its expression. Genome-wide association studies (GWAS) in different populations including European, Asian and African-American have demonstrated that a SNP near its 5ʹ end and the promoter of TOX3 gene appears to be significantly associated with breast cancer susceptibility. Furthermore, breast cancer&ndash;associated SNPs lead to enhanced FOXA1 bindings and in turn, a reduction in TOX3 gene expression. This review has highlighted the importance of TOX3 function, SNPs and its association with breast cancer risk and also its potential effects on breast cancer treatment; TOX3 plays dual and somehow conflicting roles in cancer initiation and progression which remains to be further investigated