The molecular causes of low ATM protein expression in breast carcinoma; promoter methylation and levels of the catalytic subunit of DNA-dependent protein kinase.

Abstract

AIMS:

To investigate whether aberrant methylation of the ATM promoter or loss of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) may be the underlying causes of reduced ATM protein levels often seen in breast tumours.

METHODS AND RESULTS:

Methylation-specific polymerase chain reaction was used to determine the ATM promoter status and DNA-PKcs levels were measured by immunohistochemistry. None of the 74 invasive carcinomas (ICs) studied showed ATM promoter hypermethylation, whereas promoter methylation of CDKN2A/p16 (1.8%) and GSTP1 (15.8%) was detected. Of 92 ICs examined, 68 had reduced DNA-PKcs levels, supporting previous findings that alterations in double-strand break repair are associated with breast cancer pathogenesis. Although no association was found between the DNA-PKcs and ATM scores for the series of 92 tissues and 22/24 tissues with normal DNA-PKcs had reduced ATM, 29 tumours showed low expression of both DNA-PKcs and ATM compared with normal tissues.

CONCLUSIONS:

No evidence was found that the reduction in ATM protein levels seen in breast carcinoma is the result of epigenetic silencing. However, cross-regulation between DNA-PKcs and ATM may be a possible cause in a subset of tumours and warrants further investigation.

• Authors: I Treilleux, B Chapot, S Goddard, P Pisani, S Angèle, J Hall
• Journal: Histopathology (Histopathology) Vol. 51 Issue 1 Pg. 63-9 (Jul 2007) ISSN: 0309-0167 [Print] England
• PMID: 17593081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• DNA-Activated Protein Kinase
• Protein Serine-Threonine Kinases

Topics

• Ataxia Telangiectasia Mutated Proteins
• Breast (metabolism, pathology)
• Breast Neoplasms (genetics, metabolism)
• Carcinoma, Ductal, Breast (genetics, metabolism)
• Case-Control Studies
• Catalytic Domain (genetics, physiology)
• Cell Cycle Proteins (genetics, metabolism)
• DNA Methylation
• DNA-Activated Protein Kinase (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Pilot Projects
• Promoter Regions, Genetic (genetics, physiology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)