br The results suggested PARP SNPs as
The results suggested PARP1 SNPs as SNP markers in prognosis of BC among Iranian women. Also A-G-C haplotype was found more fre-quently among BC patients rather than healthy controls. On the other hand, A-C-C and A-C-G haplotypes were more frequent in controls than cases. Moreover, rs4653734 and rs907187 were in strong LDN-193189 dis-equilibrium.
Previous studies have reported controversial results about the as-sociation of rs1136410 (Val762Ala) at PARP1 with susceptibility to BC. In a case–control investigation, Cao et al. observed no correlation be-tween Val762Ala and BC in French population (Cao et al., 2007). In turn, Tang et al. conducted a research to explore the modification ef-fects of PARP1 rs1136410 on the correlation between passive smokers
and BC risk among pre- and post-menopausal women among Chinese women, although similar differential associations were shown, the in-teractions were not significant (Tang et al., 2013). However, Alanazi et al. found that Val762Ala may play an important role in BC pro-gression in Saudi population (Alanazi et al., 2013a). Also Smith et al. examined the relationship between BC risk and the A762V (rs1136410) which was significantly associated with BC risk (Smith et al., 2008). In the present study, data do not support any association between Va-l762Ala and breast cancer risk in Iran population. Results were con-sistent with the reports of Cao et al. and Tang et al. and inconsistent with. Alanazi. et al and Smith et al. studies. Interestingly, the current findings confirmed the results of a meta-analysis including 21 studies concerning the association between the V762A and the overall risk of cancer which reported no significant association between V762A and susceptibility to cancer (Yu et al., 2012). These discrepancies may re-flect the differences in ethnic populations, suggesting further studies on the other populations.
Promoter sequences are potential sources of potential SNPs which might have crucial impacts on gene expression. A body of studies has verified association between the SNP at promoter region and BC risk. Earlier reports by Cao et al. and Zhai et al. failed to find any correlation between rs907187 and breast cancer risk in French and Chinese po-pulation, respectively (Cao et al., 2007; Zhai et al., 2015). In contrast, the present analyses indicated that rs907187 was associated with the risk of BC incidence. These challenging results possibly are due to the differences in genetic background and sample sizes. SNPs in the up-stream region of a gene can control gene expression by effecting on TF binding sites; data demonstrated that rs907187 was associated with transcriptional Regulation so that the allele substitution in the rs907187 site alters the putative binding site of E2F and E2F-4 Tran-scription factors. Analysis revealed that G allele of rs907187 might eliminate the binding site of TFs, compared with the wild-type C allele. Therefore, rs907187SNP may control the expression of PARP1 gene. The E2F transcription factor family have been characterized as reg-ulators of the cell cycle (Attwooll et al., 2004). A prior study demon-strated that the E2Fs in human cancers are important regulators of apoptosis and proliferation (Hallstrom et al., 2008). Furthermore, an investigation showed that E2Fs also play a role in relapse-free survival time in human BC (Fujiwara et al., 2011).
In silico analysis disclosed that mutant allele of rs4653734 can create a new CpG site in a CPG island of PARP1 promoter. In other words, carriers of G allele might undergo a new methylation process rather than the wild-type allele. CpG dinucleotides are possible sites of DNA methylation and it have been verified that PARP1 mRNA ex-pression decreased due to methylation of its promoter (Gao et al., 2010). CpG-SNPs may provide a possible molecular mechanism which can affect local DNA methylation and in turn influence the expression of a gene by allowing or preventing the binding of CpG methyl-binding proteins. In this case Taqi et al. suggested that CpG-SNPs probably af-fect the expression level of target genes by preventing the binding of certain proteins (Taqi et al., 2011).
In conclusion, the present study suggests association of SNPs in the studied regulatory region of PARP1 with susceptibility to BC among
Iranian women. These findings may serve the identification of high-risk breast cancer patients for further treatment and provide a close follow-up by SNP markers such as rs4653734 and rs907187. To understand the etiology of BC, ethnic background, and more epigenetic effects of PARP1 and BC incidence risk, larger sample sizes in other populations and more SNPs of PARP1 are highly recommended.
Declaration of Competing Interest