Functional implication of TRAIL -716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor.
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.
Pal
Ranjana
R
National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, Aruna Asafali Road, New Delhi, 110067, India.
Gochhait
Sailesh
S
Chattopadhyay
Shilpi
S
Gupta
Pawan
P
Prakash
Neeraj
N
Agarwal
Gaurav
G
Chaturvedi
Arun
A
Husain
Nuzhat
N
Husain
Syed Akhtar
SA
Bamezai
Rameshwar N K
RN
D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D011980:Receptors, Progesterone; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D049410:Luciferases, Renilla