The ATM gene is a target for epigenetic silencing in locally advanced breast cancer.
Several epidemiological studies on ataxia-telangiectasia families indicate that obligate ATM heterozygotes display an elevated risk for developing breast cancer. However, a molecular basis for a potential link between diminished ATM function and sporadic breast malignancy remains elusive. Here, we show that 78% (18 out of a panel of 23) of surgically removed breast tumors (stage II or greater) displayed aberrant methylation of the ATM proximal promoter region as judged by methylation-specific PCR. Aberrant methylation of the ATM promoter was independently confirmed in several tumors by bisulfite sequencing. Moreover, bisulfite sequencing indicated that this region of the genome is subject to dense methylation. Further, we found a highly significant correlation (P = 0.0006) between reduced ATM mRNA abundance, as measured by real-time RT-PCR, and aberrant methylation of the ATM gene promoter. These findings indicate that epigenetic silencing of ATM expression occurs in locally advanced breast tumors, and establish a link at the molecular level between reduced ATM function and sporadic breast malignancy.
Vo
Quynh N
QN
Department of Biochemistry and Molecular Biology, New Orleans, LA, USA.
Kim
Wan-Ju
WJ
Cvitanovic
Luke
L
Boudreau
Donald A
DA
Ginzinger
David G
DG
Brown
Kevin D
KD
D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D020868:Gene Silencing; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases