Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression: Individualized breast cancer prevention

James N. Ingle, Mohan Liu, D. Lawrence Wickerham, Daniel J. Schaid, Liewei Wang, Taisei Mushiroda, Michiaki Kubo, Joseph P. Costantino, Victor G. Vogel, Soonmyung Paik, Matthew P. Goetz, Matthew M. Ames, Gregory D. Jenkins, Anthony Batzler, Erin E. Carlson, David A. Flockhart, Norman Wolmark, Yusuke Nakamura, Richard M. Weinshilboum

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37 Citations (Scopus)

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 SNPdependent 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 estrogendependent 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.

Original languageEnglish
Pages (from-to)812-825
Number of pages14
JournalCancer Discovery
Volume3
Issue number7
DOIs
Publication statusPublished - 07-2013

All Science Journal Classification (ASJC) codes

  • Oncology

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    Ingle, J. N., Liu, M., Lawrence Wickerham, D., Schaid, D. J., Wang, L., Mushiroda, T., Kubo, M., Costantino, J. P., Vogel, V. G., Paik, S., Goetz, M. P., Ames, M. M., Jenkins, G. D., Batzler, A., Carlson, E. E., Flockhart, D. A., Wolmark, N., Nakamura, Y., & Weinshilboum, R. M. (2013). Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression: Individualized breast cancer prevention. Cancer Discovery, 3(7), 812-825. https://doi.org/10.1158/2159-8290.CD-13-0038