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The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

Oncogene volume 27, pages 2501–2506 (2008)Cite this article

Abstract

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of ‘conditional haploinsufficiency’ for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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Acknowledgements

This study was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), Finnish Cancer Society, the Sigrid Juselius Foundation, the Research and Science Foundation of Farmos, the Emil Aaltonen Foundation, the Danish Cancer Society, the Danish National Research Fund, the Danish Centre for Translational Breast Cancer Research, MSMT (Grant no. 6198959216) and the European Commission (integrated projects ‘Active p53’, ‘DNA repair’ and ‘Mutant p53’).

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Author notes

  1. J Tommiska and J Bartkova: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland

    J Tommiska, L Hautala, O Kilpivaara, H Eerola & H Nevanlinna

  2. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark

    J Bartkova, B Hofstetter, J Lukas & J Bartek

  3. Department of Pathology/HUSLAB and Haartman Institute, HUCH, Finland

    M Heinonen, A Ristimäki & P Heikkilä

  4. Genome-Scale Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    M Heinonen & A Ristimäki

  5. Department of Oncology, HUCH, Finland

    H Eerola & C Blomqvist

  6. Department of Clinical Genetics, HUCH, Finland

    K Aittomäki

  7. Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland

    K von Smitten

  8. Department of Oncology, Uppsala University Hospital, Uppsala, Sweden

    C Blomqvist

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  1. J Tommiska
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Correspondence to J Bartek or H Nevanlinna.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Tommiska, J., Bartkova, J., Heinonen, M. et al. The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene 27, 2501–2506 (2008). https://doi.org/10.1038/sj.onc.1210885

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