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The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Quynh N Vo1, Wan-Ju Kim, Luke Cvitanovic

  • 1Department of Biochemistry and Molecular Biology, New Orleans, LA, USA.

Oncogene
|November 2, 2004
PubMed

Insights

Aberrant methylation of the ATM gene promoter epigenetically silences ATM expression in advanced breast tumors. This finding links reduced ATM function to sporadic breast cancer, offering a molecular basis for increased breast cancer risk in ATM heterozygotes.

Area of Science:

  • Oncology
  • Genetics
  • Epigenetics

Background:

  • Epidemiological studies suggest ATM heterozygotes have increased breast cancer risk.
  • The molecular link between diminished ATM function and sporadic breast cancer is not well understood.

Purpose of the Study:

  • To investigate the molecular basis of ATM dysfunction in sporadic breast tumors.
  • To determine if epigenetic alterations in the ATM gene are associated with breast cancer development.

Main Methods:

  • Methylation-specific PCR and bisulfite sequencing were used to analyze ATM promoter methylation in breast tumors.
  • Real-time RT-PCR quantified ATM mRNA abundance.

Main Results:

  • Aberrant methylation of the ATM proximal promoter region was observed in 78% of stage II or greater breast tumors.
  • Dense methylation of the ATM promoter region was confirmed by bisulfite sequencing.
  • A significant correlation (P = 0.0006) was found between aberrant ATM promoter methylation and reduced ATM mRNA levels.

Conclusions:

  • Epigenetic silencing of ATM expression occurs in locally advanced breast tumors.
  • Aberrant ATM promoter methylation provides a molecular link between reduced ATM function and sporadic breast malignancy.

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