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Germline BRCA2 mutations in female carriers confer a cumulative breast cancer risk at age 70 years of 49% (95% CI: 40–57%), an ovarian cancer risk of 18% (95% CI: 13–23%), and a moderate increased risk of pancreatic cancer (Chen and Parmigiani, 2007). Although the available evidence is not sufficient to decisively conclude that the clinical outcome of women with BRCA1/2-associated breast cancer differs significantly from those of women with sporadic tumours, BRCA1-associated breast cancer often manifests adverse outcome features. Establishment of pre-clinical models, which accurately reflect the genetic and phenotypic features of primary tumours, and their response to treatment, is an important step in identifying novel therapeutic targets and testing new treatment modalities. New strategies may take advantage of the specific DNA repair defects inherent in BRCA-deficient cells, such as the defect in homologous recombination. In fact, most of the insights into the functions of the BRCA2 protein have included key insights from studies of mice by the use of gene targeting and from studies of altered mouse embryonic cells (Evers and Jonkers, 2006). BRCA2 has a key role in DNA double-strand break repair and cell-cycle control. BRCA2-related defects are associated with chromosomal abnormalities, a hallmark of the genomic instability that could foster tumourigenesis. Moreover, BRCA2 participates in the regulation of mitosis and cytokinesis that contribute to numerical chromosomal stability. Although conventional, non-conditional, mouse mutants might be used to model familial forms of cancer, they do not mimic sporadic tumourigenesis because the initiating mutation is present in all cells of the body, including those that constitute the tumour microenvironment. Moreover, embryonic lethality and development of non-epithelial tumours are another important limitation of genetically mutated Brca2 mice. Some murine Brca2 mutant mammary tumour models develop mammary tumours with histopathological features that are significantly different to their human counterparts. Although some studies report a strikingly similar histopathology in BRCA1 null breast tumours from mice and humans (Dennis, 1999; Xu et al, 1999), their relevance to the human situation remains to be demonstrated. The most used human BRCA2-mutated model is the CAPAN1 pancreatic cell line that is mainly used to understand drug resistance in BRCA1/2 mutation carrier, as well as in defining functionally important domains within BRCA2 (Edwards et al, 2008). To date, only one BRCA2-mutated breast cancer xenografts (MX1) is available, (Donawho et al, 2007) but its characterisation has not been described in detail. Genetic testing to identify BRCA1/2 mutations is widely available and commonly employed. As a result, increasing numbers of women are aware that they are mutation carriers at the time of their cancer diagnosis. Unfortunately, current knowledge is not sufficient to mandate specific local or systemic treatments that are tailored to BRCA1/2 mutation carriers. In fact, the available studies examining the issue of whether BRCA1/2-associated breast cancer should be treated differently from sporadically occurring, non-familial disease are almost exclusively retrospective and limited by small size and various ascertainment biases. Recently, inhibitors of the DNA repair proteins, poly(ADP-ribose) polymerase 1 and 2 (PARP1/2), have been shown to be selectively cytotoxic to tumour cells with BRCA1 or BRCA2 deficiency. Preclinical data, including that generated with a limited array of tumour cell line xenografts, suggest that PARP inhibitors can act as single agents to selectively kill cancers with BRCA1 or BRCA2 mutations, and phase I clinical trial results confirm that PARP inhibitors have some single-agent activity in cancers with BRCA1/2 mutations (Fong et al, 2009). However, little is known about the long-term effects of these drugs and it seems likely that some tumours may have de novo resistance or acquired resistance (Ashworth, 2008). Thus, definitive answers remain elusive, and preclinical evaluation of new targeted therapy is limited by the lack of suitable preclinical models (Robson, 2007a). Here, we report the establishment and characterisation of a novel xenograft, human breast cancer xenograft (HBCx-17) established from a breast cancer in a woman carrying a BRCA2 germline mutation. We show that this xenograft accurately reflects the genetic and the phenotypic features of the primary tumour, thus providing a new model to test new therapies for BRCA2-mutated patients.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.