Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens.
Functional inactivation of BRCA1 is an important mechanism involved in breast cancer pathogenesis. Mutation is often responsible for BRCA1 inactivation in familial breast cancer, but is not responsible for the decreased levels of BRCA1 seen in a subset of sporadic breast cancer patients. To determine if aberrant cytosine methylation of the BRCA1 promoter is associated with decreased BRCA1 gene expression in human breast cancer, high resolution bisulfite sequence analysis was used to analyze the cytosine methylation status of the BRCA1 promoter in 21 axillary node negative breast cancer patients with known levels of BRCA1 expression. Aberrant cytosine methylation of the BRCA1 promoter was detected in three of 21 patient specimens. These three specimens also expressed the lowest levels of BRCA1. Results from this analysis show that aberrant cytosine methylation of the BRCA1 promoter is directly correlated with decreased levels of BRCA1 expression in human breast cancer, and suggest that epigenetic silencing may be one mechanism of transcriptional inactivation of BRCA1 in sporadic mammary carcinogenesis.
Rice
J C
JC
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
Ozcelik
H
H
Maxeiner
P
P
Andrulis
I
I
Futscher
B W
BW
D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D019398:Genes, BRCA1 / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D003596:Cytosine