SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer.

Abstract

INTRODUCTION:

The MDM2 promoter polymorphism (SNP309T > G) extends a binding site for the transcription factor Sp1 and has been linked to elevated cancer risk and/or young age at cancer diagnosis, especially in females. Recently, we reported an adjacent polymorphism (SNP285G > C). SNP285C antagonises the effect of SNP309G by reducing Sp1 binding and lowers the risk of breast and ovarian cancer.

METHODS:

We assessed the potential gender specificity in the effect of this polymorphism. We performed in silico predictions of transcription factor binding sites in the MDM2 promoter and analysed MDM2 SNP285 and SNP309 status in two independent cohorts of endometrial (n = 438 and 472) and 666 prostatic cancer patients, and compared to 3.140 healthy controls.

RESULTS:

We identified three oestrogen-receptor binding elements (EREs) within the MDM2 intronic promoter, one of which overlapping the Sp1 binding-site harbouring SNP285. The SNP285C/309G haplotype was associated with a reduced Odds Ratio (OR) for endometrial cancer (OR1: 0.55; Confidence Interval (CI) 0.32-0.97; OR2: 0.65; CI 0.40-1.08, especially for ER+ tumours; OR: 0.48; CI 0.28-0.87) but not for prostatic cancer among SNP309TG heterozygotes. SNP309G (SNP309TG or SNP309GG genotype) was associated with a moderately increased risk of endometrial cancer (OR: 1.17; CI 1.00-1.37) compared to SNP309TT homozygotes. Removing individuals harbouring the SNP309G-counteracting SNP285C polymorphism from the analysis strengthened this association (OR: 1.20; CI 1.02-1.41).

CONCLUSION:

The finding of an ERE overlapping with the Sp1-binding site affected by SNP285, taken together with the significant impact of SNP285 on the risk of breast, ovarian and now endometrial cancer but not prostatic cancer, suggests a gender specific effect of SNP285C on cancer risk.

• Authors: Stian Knappskog, Jone Trovik, Janusz Marcickiewicz, Solveig Tingulstad, Annetine C Staff, MoMaTEC study group, Pål Romundstad, Kristian Hveem, Lars Vatten, Helga B Salvesen, Per E Lønning
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 13 Pg. 1988-96 (Sep 2012) ISSN: 1879-0852 [Electronic] England
• PMID: 22119201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Base Sequence
• Binding Sites (drug effects)
• Endometrial Neoplasms (genetics, metabolism)
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Prostatic Neoplasms (genetics, metabolism)
• Proto-Oncogene Proteins c-mdm2 (genetics)
• Receptors, Estrogen (metabolism)
• Risk
• Sex Factors
• Sp1 Transcription Factor (metabolism)