TY - JOUR
T1 - Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression
T2 - Individualized breast cancer prevention
AU - Ingle, James N.
AU - Liu, Mohan
AU - Lawrence Wickerham, D.
AU - Schaid, Daniel J.
AU - Wang, Liewei
AU - Mushiroda, Taisei
AU - Kubo, Michiaki
AU - Costantino, Joseph P.
AU - Vogel, Victor G.
AU - Paik, Soonmyung
AU - Goetz, Matthew P.
AU - Ames, Matthew M.
AU - Jenkins, Gregory D.
AU - Batzler, Anthony
AU - Carlson, Erin E.
AU - Flockhart, David A.
AU - Wolmark, Norman
AU - Nakamura, Yusuke
AU - Weinshilboum, Richard M.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-13-0038
DO - 10.1158/2159-8290.CD-13-0038
M3 - Article
C2 - 23764426
AN - SCOPUS:84880265900
SN - 2159-8274
VL - 3
SP - 812
EP - 825
JO - Cancer Discovery
JF - Cancer Discovery
IS - 7
ER -
