Breast Cancer Research and Treatment

, Volume 126, Issue 2, pp 333–343 | Cite as

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

  • Ranjana Pal
  • Sailesh Gochhait
  • Shilpi Chattopadhyay
  • Pawan Gupta
  • Neeraj Prakash
  • Gaurav Agarwal
  • Arun Chaturvedi
  • Nuzhat Husain
  • Syed Akhtar Husain
  • Rameshwar N. K. BamezaiEmail author
Preclinical study


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.


TRAIL Polymorphism Apoptosis 



The authors would like to thank the patient and control subjects for their participation. RP is grateful to the Council of Scientific and Industrial Research, New Delhi, India, for the pre-doctoral fellowship. RB was supported by a research grant from the University Grants Commission to the National Centre of Applied Human Genetics and the University with Potential of Excellence projects.

Supplementary material

10549_2010_900_MOESM1_ESM.doc (110 kb)
Supplementary material 1 (DOC 92 kb)
10549_2010_900_MOESM2_ESM.jpg (23 kb)
Haploview graph showing LD between TRAIL locus −760/−716 and −716/−692 in patients and control (JPG 22 kb)
10549_2010_900_MOESM3_ESM.jpg (80 kb)
Real time PCR data of extrinsic and intrinsic apoptotic pathway genes with respect to TRAIL −716 genotype (JPG 80 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Ranjana Pal
    • 1
  • Sailesh Gochhait
    • 1
  • Shilpi Chattopadhyay
    • 1
  • Pawan Gupta
    • 2
  • Neeraj Prakash
    • 3
  • Gaurav Agarwal
    • 4
  • Arun Chaturvedi
    • 5
  • Nuzhat Husain
    • 5
  • Syed Akhtar Husain
    • 6
  • Rameshwar N. K. Bamezai
    • 1
    • 7
    Email author
  1. 1.National Centre of Applied Human Genetics, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
  2. 2.Dharamshila Cancer Hospital and Research CentreDelhiIndia
  3. 3.Rajiv Gandhi Cancer Institute and Research CenterNew DelhiIndia
  4. 4.Sanjay Gandhi Postgraduate Institute of Medical SciencesLucknowIndia
  5. 5.Chhatrapati Shahuji Maharaj Medical UniversityLucknowIndia
  6. 6.Human Genetics Laboratory, Department of BiosciencesJamia Milia IslamiaNew DelhiIndia
  7. 7.SMVDUKatraJammu and KashmirIndia

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