title: The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Tommiska
authors.forename: J
authors.initials: J
authors.lastname: Bartkova
authors.forename: M
authors.initials: M
authors.lastname: Heinonen
authors.forename: L
authors.initials: L
authors.lastname: Hautala
authors.forename: O
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: H
authors.initials: H
authors.lastname: Eerola
authors.forename: K
authors.initials: K
authors.lastname: Aittomäki
authors.forename: B
authors.initials: B
authors.lastname: Hofstetter
authors.forename: J
authors.initials: J
authors.lastname: Lukas
authors.forename: K
authors.initials: K
authors.lastname: von Smitten
authors.forename: C
authors.initials: C
authors.lastname: Blomqvist
authors.forename: A
authors.initials: A
authors.lastname: Ristimäki
authors.forename: P
authors.initials: P
authors.lastname: Heikkilä
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.forename: H
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000172:deficiency* / Q000378:metabolism; D024682:BRCA2 Protein / Q000172:deficiency* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human