DNA hypermethylation of ESR1 and PGR in breast cancer: pathologic and epidemiologic associations.
Improved understanding of the etiology of estrogen receptor-alpha (ERalpha)-negative and progesterone receptor (PR)-negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERalpha and PR promoters in the pathogenesis of ERalpha-negative and PR-negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based case-control 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 ERalpha and PR, tumor characteristics, and breast cancer risk factors. 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 ERalpha (beta = -0.26; P < 0.0001) and PR (beta = -0.25; P < 0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERalpha (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 ERalpha and PR expression.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA. mia.gaudet@einstein.yu.edu
Mia M
MM
Gaudet
Mihaela
M
Campan
Jonine D
JD
Figueroa
Xiaohong R
XR
Yang
Jolanta
J
Lissowska
Beata
B
Peplonska
Louise A
LA
Brinton
David L
DL
Rimm
Peter W
PW
Laird
Montserrat
M
Garcia-Closas
Mark E
ME
Sherman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; C439067:MRFAP1 protein, human; D009687:Nuclear Proteins