Identification Of An Atm Activation Subtype In Pten Mutant Breast Tumours.

Abstract Background PTEN is frequently lost in cancer cells through genetic mutation or epigenetic silencing. Loss of PTEN function has been widely reported to cause up-regulation of the PI3K/AKT signalling pathway resulting in increased cell growth, proliferation and survival. More recently it has been reported that PTEN null cells demonstrate genomic instability through increased ROS and oxidative stress induced DNA damage. The aim of this study was to identify a biomarker for PTEN status in human breast cancers. Materials and Methods A metagene representing ATM activation was generated from public cell line data of AT fibroblasts treated with gamma-irradiation. This was used to perform hierarchical clustering analysis of a public DNA microarray profiling dataset with known PTEN IHC status. The metagene was validated in PTEN wildtype and null breast cancer cell lines. Results We found that PTEN null cells have elevated levels of ROS and furthermore activation of the DNA damage signalling kinase, ATM. In agreement with this, the ATM metagene signature correlated with PTEN mutation in breast cancer tumours. Scoring of PTEN wildtype and null breast cancer cell lines using the metagene correlated with ATM activation and sensitivity to inhibition of ATM. Furthermore we show that inhibition of ATM caused DNA damage, cell cycle arrest and apoptosis in PTEN deficient cells suggesting a novel therapeutic strategy. Conclusion These observations suggest that ATM may represent a therapeutic target in PTEN deficient tumours and furthermore ATM activation may also be an important biomarker of PTEN mutation or loss in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-12.