The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians

Cancer Cell. 2011 Feb 15;19(2):273-82. doi: 10.1016/j.ccr.2010.12.019.

Abstract

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease*
  • Haplotypes*
  • Humans
  • Ovarian Neoplasms / genetics*
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic*
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Receptors, Estrogen / metabolism
  • Sp1 Transcription Factor / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • White People*

Substances

  • Receptors, Estrogen
  • Sp1 Transcription Factor
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2