Hormones and Cancer

, Volume 3, Issue 1–2, pp 37–43 | Cite as

Functional Characterization of a Genetic Polymorphism in the Promoter of the ESR2 Gene

  • Santosh Philips
  • Alexandra Richter
  • Steffi Oesterreich
  • James M. Rae
  • David A. Flockhart
  • Narayanan B. Perumal
  • Todd C. Skaar


The ESR2 gene encodes the estrogen receptor beta protein. Several studies have shown that genetic variants in the ESR2 gene are associated with a variety of clinical phenotypes. However, very little is known about the functional significance of ESR2 genetic variants. We used a bioinformatics approach to identify regions of the ESR2 promoter that is evolutionarily conserved across the genomes of several species. We resequenced 1.6 kb of the ESR2 gene which included 0.8 kb of the promoter, 0.3 kb of exon ON, and 0.5 kb of the following intron. We identified five single-nucleotide polymorphisms (SNPs) in the ESR2 promoter and one SNP in the intron. Phase analysis indicated that the SNPs likely exist in 11 different haplotypes. Three of the SNPs (rs8008187, rs3829768, rs35036378) were predicted to alter transcription factor binding sites in the ESR2 promoter. All three were detected only in African American subjects. The rs35036378 SNP was in the TATA box and was highly conserved across species. ESR2 promoter reporter assays in LNCaP and SKBR3 cell lines showed that the variant construct containing the rs35036378 SNP allele had approximately 50% less activity relative to the wild-type construct. We conclude that the rs35036378 SNP appears to cause a reduced promoter activity of the ESR2 gene.


ESR2 SNPs TATA box Promoter polymorphism 



This research was supported by NIH-PGRN (5U01GM061373, D.A.F.), NIH-NIGMS (U01GM061373, 5K24RR020815), NIH-NCRR M01-RR000042 (University of Michigan), M01-RR020359 (Georgetown University), M01-RR00750 (Indiana University) and the Pennsylvania Department of Health, Commonwealth Universal Research Enhancement (C.U.R.E.) Program (SO). We would like to acknowledge the additional COBRA investigators, Daniel Hayes, N. Lynn Henry, Vered Stearns, and Anna Maria Storniolo, who were the clinical investigators on the tamoxifen trial from which some of the samples were used in this study.

Conflict of Interest

We declare no conflict of interest.

Supplementary material

12672_2011_86_MOESM1_ESM.doc (36 kb)
ESM. 1 (DOC 36 kb)


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Santosh Philips
    • 1
    • 4
  • Alexandra Richter
    • 2
  • Steffi Oesterreich
    • 2
  • James M. Rae
    • 3
  • David A. Flockhart
    • 1
  • Narayanan B. Perumal
    • 4
  • Todd C. Skaar
    • 1
  1. 1.Department of MedicineDivision of Clinical Pharmacology, Indiana University School of MedicineIndianapolisUSA
  2. 2.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  4. 4.Indiana University School of InformaticsIndianapolisUSA

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