Germ-line mutations in BRCA1 predispose to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify 53BP1 as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Importantly, loss of 53BP1 partially restores the homologous recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.

Inhibition of PARP is a promising therapeutic strategy for homologous recombinationdefi cient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-defi cient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug effl ux transporter. Here, we show that tumorspecifi c genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-defi cient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-defi cient mammary tumors and that the risk of relapse of BRCA1-defi cient tumors can be effectively minimized by using optimized PARP inhibitors. SIGNIFICANCE:In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are defi cient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-defi cient tumors to PARP inhibitors.Cancer Discov; 3(1);[68][69][70][71][72][73][74][75][76][77][78][79][80][81]

BRCA1 plays a critical role in the regulation of homologous recombination (HR)-mediated DNA double-strand break repair. BRCA1-deficient cancers have evolved to tolerate loss of BRCA1 function. This renders them vulnerable to agents, such as PARP inhibitors, that are conditionally 'synthetic lethal' with their underlying repair defect. Recent studies demonstrate that BRCA1-deficient cells may acquire resistance to these agents by partially correcting their defect in HR-mediated repair, either through reversion mutations in BRCA1 or through 'synthetic viable' loss of 53BP1. These findings and their clinical implications will be reviewed in this article.

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Background: Abnormalities in the DNA repair mechanism have been proposed to play a central role in the development of breast cancers. However the specific mechanism underlying DNA repair defects in sporadic breast cancer are mostly unknown. As 53BP1 plays a critical role in DNA repair response and has been identified as a potential tumor suppressor, its expression in basal-like breast cancer cell lines and clinical samples was investigated.Experimental Design: mRNA expression of 53BP1 was investigated in publicly available gene expression data sets. Protein expression of 53BP1 was evaluated in a large set of clinically annotated breast cancer specimens by immunohistochemistry. Analysis of 53BP1 and related proteins was performed in a set of human and mouse breast cancer cell lines.Results: Gene expression analysis demonstrated that a subset of basal-like breast cancer had decreased expression of 53BP1. Analysis of over 400 breast cancers in a tissue microarray showed that loss of 53BP1 staining was almost exclusively found in tumors that lacked ER, PR and HER2 expression; this "triple-negative" phenotype is characteristic of BLC. Approximately 42% of "triple-negative" breast cancers have abnormally low levels of 53BP1, while <2% of tumor that express either ER or HER2 lack 53BP1 expression. Tumors that have low 53BP1 expression are associated with worse distant metastasis free survival when compared to tumors with normal 53BP1 expression. A set of breast cancer cell lines with abnormal 53BP1 expression was also identified. 53BP1 abnormalities were present in some tumors and cell lines with known BRCA1 mutations.Discussion: These data suggest that a subset of basal-like breast cancers lack normal 53BP1 expression and imply that these tumors may have profound defects in DNA repair/check point function that could be exploited therapeutically. As 53BP1 abnormalities were found in some tumors with known BRCA1 mutations, this suggests that loss of 53BP1 may cooperate with abnormalities in the BRCA1-related DNA repair pathways in the pathogenesis of basal-like breast cancers. Data regarding the molecular mechanisms underlying 53BP1 abnormalities in breast cancer cell lines and samples will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1122.

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