Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention

Cancer Discov. 2013 Jul;3(7):812-25. doi: 10.1158/2159-8290.CD-13-0038. Epub 2013 Jun 13.

Abstract

The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high-risk women by 50%, but this U.S. Food and Drug Administration-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single-nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cathepsins / genetics*
  • DNA-Binding Proteins / genetics*
  • Estrogen Receptor Modulators / administration & dosage
  • Female
  • Genome-Wide Association Study
  • Humans
  • Polymorphism, Single Nucleotide
  • Precision Medicine
  • Proteins
  • Raloxifene Hydrochloride / administration & dosage
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Selective Estrogen Receptor Modulators / metabolism
  • Tamoxifen / administration & dosage

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • DNA-Binding Proteins
  • Estrogen Receptor Modulators
  • Proteins
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • ornithine decarboxylase antizyme
  • Tamoxifen
  • Raloxifene Hydrochloride
  • Cathepsins
  • CTSO protein, human