TY - JOUR
T1 - DNA hypermethylation of ESR1 and PGR in breast cancer
T2 - Pathologic and epidemiologic associations
AU - Gaudet, Mia M.
AU - Campan, Mihaela
AU - Figueroa, Jonine D.
AU - Yang, Xiaohong R.
AU - Lissowska, Jolanta
AU - Peplonska, Beata
AU - Brinton, Louise A.
AU - Rimm, David L.
AU - Laird, Peter W.
AU - Garcia-Closas, Montserrat
AU - Sherman, Marke
PY - 2009/11
Y1 - 2009/11
N2 - Improved understanding of the etiology of estrogen receptor-α (ERα)-negative and progesterone receptor (PR)-negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERα and PR promoters in the pathogenesis of ERα-negative and PR-negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based casecontrol study. DNA extracted from fixed tumor tissue cores was tested using MethyLight to assess DNA methylation at four CpG islands: ESR1 promoters A and B; PGR promoters A and B; and a CpG shore, ESR1 promoter C. DNA methylation results were compared with levels of ERα and PR, tumor characteristics, and breast cancer riskfactors. We observed mild to moderate DNA methylation levels in most tumors for ESR1 promoters A and B and PGR promoter B, and a few tumors showed mild methylation in PGR promoter A. In contrast, ESR1 promoter C showed a wide range of methylation and was weakly correlated with lower expression levels of ERα (β = -0.26; P < 0.0001) and PR (β = -0.25; P < 0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERα (A, Fisher's test P = 0.0001; B, P = 0.033) and PR levels (A, P = 0.0006; B, P = 0.001). Our data suggest that the relationships between DNA methylation of ESR1 and PGR promoters and protein expression are weak and unlikely to represent a predominant mechanism of receptor silencing. In contrast to CpG islands, ESR1 promoter C showed a wider range of methylation levels and inverse associations with ERα and PR expression.
AB - Improved understanding of the etiology of estrogen receptor-α (ERα)-negative and progesterone receptor (PR)-negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERα and PR promoters in the pathogenesis of ERα-negative and PR-negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based casecontrol study. DNA extracted from fixed tumor tissue cores was tested using MethyLight to assess DNA methylation at four CpG islands: ESR1 promoters A and B; PGR promoters A and B; and a CpG shore, ESR1 promoter C. DNA methylation results were compared with levels of ERα and PR, tumor characteristics, and breast cancer riskfactors. We observed mild to moderate DNA methylation levels in most tumors for ESR1 promoters A and B and PGR promoter B, and a few tumors showed mild methylation in PGR promoter A. In contrast, ESR1 promoter C showed a wide range of methylation and was weakly correlated with lower expression levels of ERα (β = -0.26; P < 0.0001) and PR (β = -0.25; P < 0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERα (A, Fisher's test P = 0.0001; B, P = 0.033) and PR levels (A, P = 0.0006; B, P = 0.001). Our data suggest that the relationships between DNA methylation of ESR1 and PGR promoters and protein expression are weak and unlikely to represent a predominant mechanism of receptor silencing. In contrast to CpG islands, ESR1 promoter C showed a wider range of methylation levels and inverse associations with ERα and PR expression.
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U2 - 10.1158/1055-9965.EPI-09-0678
DO - 10.1158/1055-9965.EPI-09-0678
M3 - Article
C2 - 19861523
AN - SCOPUS:72749106092
SN - 1055-9965
VL - 18
SP - 3036
EP - 3043
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 11
ER -