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

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

1. James N. Ingle1,


2. Mohan Liu2,


3. D. Lawrence Wickerham4,6,


4. Daniel J. Schaid3,


5. Liewei Wang2,


6. Taisei Mushiroda11,


7. Michiaki Kubo11,


8. Joseph P. Costantino6,7,8,


9. Victor G. Vogel9,


10. Soonmyung Paik6,


11. Matthew P. Goetz1,


12. Matthew M. Ames2,


13. Gregory D. Jenkins3,


14. Anthony Batzler3,


15. Erin E. Carlson3,


16. David A. Flockhart10,


17. Norman Wolmark5,6,


18. Yusuke Nakamura11 and


19. Richard M. Weinshilboum2

+ Author Affiliations

1. 
   Authors' Affiliations:¹Division of Medical Oncology, ²Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, and ³Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; ⁴Section of Cancer Genetics and Prevention and ⁵Department of Human Oncology, Allegheny General Hospital; ⁶National Surgical Adjuvant Breast and Bowel Project (NSABP), ⁷NSABP Biostatistical Center, ⁸Department of Biostatistics, Graduate School of Public Health, and ⁹Department of Medical Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania; ¹⁰Indiana University, Indianapolis, Indiana; ¹¹RIKEN Center for Genomic Medicine, Tokyo, Japan
   
   

+ Author Notes

• 
  Current affiliation for V.G. Vogel: Cancer Institute, Geisinger Health System, Danville, Pennsylvania.
  
  


• 
  Current affiliation for Y. Nakamura: University of Chicago, Chicago, Illinois.
  
  

1. Corresponding Author:
   James N. Ingle, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. Phone: 507-284-4857; Fax: 507-284-1803; E-mail: ingle.james@mayo.edu

1. 
   J.N. Ingle and M. Liu contributed equally to this work.
   
   

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.

SIGNIFICANCE: This study identified novel, functionally polymorphic genes involved in the estrogen-dependent regulation of BRCA1 expression, as well as a novel mechanism for genetic variation in SERM therapeutic effect. These observations, and definition of their underlying mechanisms, represent steps toward pharmacogenomically individualized SERM breast cancer prevention. Cancer Discov; 3(7); 1–14. ©2013 AACR.

Footnotes

• 
  Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).
  
  

• Received January 30, 2013.


• Revision received April 2, 2013.


• Accepted April 10, 2013.

©2013 American Association for Cancer Research