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.