Functional implication of TRAIL 2716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Ranjana Pal Sailesh Gochhait Shilpi Chattopadhyay Pawan Gupta Neeraj Prakash Gaurav Agarwal Arun Chaturvedi Nuzhat Husain Syed Akhtar
- چاپ و سال / کشور: 2010
Description
Recently, TRAIL function has been elucidated beyond its known classical role of mediating cellular homeostasis and immune surveillance against transformed cells. Here, we show how CC genotype of -716 TRAIL promoter SNP rendered risk for sporadic breast cancer as compared to the CT and TT genotypes (Precessive model = 0.018, OR = 1.4, 95% CI = 1.1–1.9; Pallele model = 0.010, OR = 1.3, 95% CI = 1.1–1.7). The in silico prediction of the introduction of core Sp1/Sp3-binding motif suggested the functional significance of the SNP variation. This functional implication was validated by luciferase assay in HeLa (P = 0.026), MCF-7 (P = 0.022), HepG2 (P = 0.024), and HT1080 (P = 0.030) cells and also by real-time expression studies on tumor tissues (P = 0.01), revealing the transcriptionally repressed status of -716 T when compared to -716 C allele. The SNP–SNP interactions reflected an enhanced protective effect of CT and TT genotypes with the protective genetic backgrounds of TP53-BRCA2 (P = 0.002, OR = 0.2, 95% CI = 0.1–0.6), IFNG (P = 0.0000002, OR = 0.3, 95% CI = 0.2–0.4), and common variant Casp8 (P = 0.0003, OR = 0.5, 95% CI = 0.3– 0.7). Interestingly, a comparison with clinical parameters showed overrepresented CT and TT genotypes in progressing (P = 0.041) and ER/PR negative tumors (P = 0.024/ 0.006). This was explained by increased apoptotic index, calculated as a ratio of selected pro-apoptotic and antiapoptotic gene expression profiles, in CC genotyped tumors, favoring either intrinsic (P = 0.008,0.018) or extrinsic (P = 0.025,0.217) pathway depending upon the ER/PR status. Our study reveals for the first time that a promoter SNP of TRAIL functionally modulates the gene and consequently its role in breast cancer pathogenesis, cautioning to consider the-716 TRAIL SNP status in patients undergoing TRAIL therapy.
Breast Cancer Res Treat (2011) 126:333–343 Received: 8 November 2009 / Accepted: 15 April 2010 / Published online: 5 May 2010 Springer Science+Business Media, LLC. 2010
