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01-04-2011 | Preclinical study

Functional implication of TRAIL −716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor

Authors: Ranjana Pal, Sailesh Gochhait, Shilpi Chattopadhyay, Pawan Gupta, Neeraj Prakash, Gaurav Agarwal, Arun Chaturvedi, Nuzhat Husain, Syed Akhtar Husain, Rameshwar N. K. Bamezai

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

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 (P _{recessive model} = 0.018, OR = 1.4, 95% CI = 1.1–1.9; P _{allele 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 anti-apoptotic 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.

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Title: Functional implication of TRAIL −716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor
Authors: Ranjana Pal
Sailesh Gochhait
Shilpi Chattopadhyay
Pawan Gupta
Neeraj Prakash
Gaurav Agarwal
Arun Chaturvedi
Nuzhat Husain
Syed Akhtar Husain
Rameshwar N. K. Bamezai
Publication date: 01-04-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-0900-5

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