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Mouse Models of BRCA1 and BRCA2 Deficiency

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Mouse Models of BRCA1 and BRCA2 Deficiency Oncogene (2006) 25, 5885–5897 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects B Evers and J Jonkers Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Germline mutations in BRCA1 and BRCA2 are respon- risk of up to 80% for developing breast cancer and sible for a large proportion of hereditary breast and also display increased risk for ovarian cancer (B40% ovarian cancers. Soon after the identification of both for BRCA1 mutation carriers and B20% for BRCA2 genes in the mid-1990s, investigators set out to develop carriers, respectively) (Narod and Foulkes, 2004). In mouse models for the associated disease. Whereas most breast cancers arising in BRCA1/2 carriers, conventional Brca1 and Brca2 mouse mutants did not inactivation of the wild-type allele has occurred by reveal a strong phenotype in a heterozygous setting, means of loss of heterozygosity, thus abolishing normal most homozygous mutations caused embryonic lethality. protein expression (Smith et al., 1992; Collins et al., Consequently, development of mouse models for BRCA- 1995). BRCA1 tumors show a rather uniform tumor associated tumorigenesis required the generation of tissue- type of high-grade invasive ductal carcinomas, which are specific conditional knockout animals. In this review, we usually estrogen receptor (ER) and HER2/neu negative give an overview of the conventional and the conditional (Chappuis et al., 2000; Phillips, 2000). These properties mouse models of BRCA1 and BRCA2 deficiency gener- are reminiscent of ‘triple-negative’ (ER-, progesterone ated over the last decade, as well as the contribution receptor (PR)- and HER2/neu-negative) basal-like of these models to our understanding of the biological sporadic breast cancers (Livasy et al., 2006). Indeed, and molecular functions of BRCA1 and BRCA2. The cluster analysis of gene expression data from human most advanced mouse models for BRCA1- and BRCA2- breast cancers revealed strong similarity between associated tumorigenesis mimic human disease to the BRCA1-mutated tumors and basal-like breast cancers extent that they can be used in studies addressing (Sorlie et al., 2003). BRCA2 deficient tumors, on the clinically relevant questions. These models will help to other hand, show larger variety in histological classifica- resolve yet unanswered questions and to translate our tion and are not easily distinguished from the overall increasing knowledge of BRCA1 and BRCA2 biology into spectrum of sporadic tumors. While parity in the general clinical practice. population has been associated with decreased breast Oncogene (2006) 25, 5885–5897. doi:10.1038/sj.onc.1209871 cancer risk, parity per se was not found to influence risk in BRCA1 mutation carriers, although multiparity did Keywords: BRCA1; BRCA2; breast cancer; tumor seem to protect as well. For BRCA2, data suggest suppressor; mouse model that increasing parity is associated with increased risk of breast cancer. BRCA2-mutation carriers also have an increased risk of developing pregnancy-associated breast cancer (Cullinane et al., 2005). Introduction Breast cancer is the most common malignancy in Conventional Brca1 and Brca2 mutants women of the Western world, affecting up to 10% of the female population (Alberg and Helzlsouer, 1997). Following identification of the BRCA1 and BRCA2 An estimated 5% of all breast cancers is ascribed to breast cancer genes in humans, investigators sought hereditary predisposition. Intensive research in the early to recapitulate the effects of these genetic lesions 1990s has led to the identification of two major breast in mouse models. Several groups have generated a cancer susceptibility genes, BRCA1 (Futreal et al., 1994; range of conventional Brca1 and Brca2 knockout mice Miki et al., 1994) and BRCA2 (Wooster et al., 1995; with mutations in different portions of the genes (see Tavtigian et al., 1996). Individuals carrying mutations in Figures 1 and 2). Somewhat disappointingly, none of one allele of either BRCA1 or BRCA2 have a lifetime these mouse mutants showed a strong tumor predispos- ing phenotype in a heterozygous setting. When bred to homozygosity, most Brca1 and Brca2 mouse mutants Correspondence: Dr J Jonkers, Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, displayed severe embryonic lethal phenotypes. Although The Netherlands. these traits have hindered in vivo analysis of tumor E-mail: [email protected] suppressor functions of Brca1 and Brca2, conventional Mouse models of BRCA1/2 deficiency B Evers and J Jonkers 5886 Figure 1 Conventional and conditional Brca1 mutant alleles generated to date. Exon compositions for the predicted splice products are indicated, including the Brca1-D11 splice variant and the – for mice putative – Brca1-IRIS product. A w indicates that the predicted transcript contains a premature stop, resulting from a frame shift. In that case only the exons encoding the (predicted) truncated protein product are indicated. The bottom panel shows all BRCA1 splice variants known to exist in humans and mice. BRCA1 lacks exon 4, which had been erroneously identified during the initial cloning of the BRCA1 gene (Miki et al., 1994). EL: embryonic lethality day. mouse mutants have provided valuable insight into their observation that Brca-deficiency results in chromosomal biological roles. instability and increased sensitivity to DNA-damaging agents in cultured mouse cells (Sharan et al., 1997; Patel Functional clues et al., 1998; Shen et al., 1998; Tutt et al., 1999) and in Soon after the generation of Brca1 and Brca2 mouse living animals (Tutt et al., 2002). These phenotypes were mutants, it was acknowledged that the embryonic subsequently attributed to defects in repair of double- lethality of Brca1-deficient mice closely resembled the strand breaks (DSBs) by homologous recombination phenotype of mouse mutants of Rad51, a homologue (HR) (Moynahan et al., 1999, 2001; Xia et al., 2001). of the bacterial RecA protein known to be involved Whereas initial studies in Brca1 and Brca2 mouse in DNA damage repair (Lim and Hasty, 1996). mutants have highlighted similarities between both Subsequently, Rad51, Brca1 and Brca2 proteins were proteins, other research efforts have also revealed clear shown to have similar expression patterns during mouse differences (Venkitaraman, 2002). BRCA1 appears to embryogenesis (Lane et al., 1995; Marquis et al., 1995; be more of a signal integrator, linking together sensors Sharan et al., 1997; Blackshear et al., 1998) and during and response mechanisms of several types of DNA cell-cycle progression (Rajan et al., 1996; Chen et al., damage. In contrast, BRCA2 is thought to be more 1997). In addition, Brca1, Brca2 and Rad51 were found directly involved in homology-directed DSB repair, as it to co-localize in nuclear dot patterns (Scully et al., 1997; mediates the formation of a RAD51-DNA nucleopro- Chen et al., 1998) and to interact with each other tein filament that catalyzes strand invasion during HR (Scully et al., 1997; Sharan et al., 1997; Chen et al., (Pellegrini and Venkitaraman, 2004). 1998), suggesting a role for the BRCA proteins in For BRCA1, a wealth of data describes many DNA-damage repair. This notion was supported by the interactions with other proteins, as well as many Oncogene Mouse models of BRCA1/2 deficiency B Evers and J Jonkers 5887 Figure 2 Conventional and conditional Brca2 mutant alleles generated to date. The exon composition of the predicted splice product from the mutant allele is indicated. A w indicates that the predicted transcript contains a premature stop, resulting from a frame shift. In that case only the exons encoding the (predicted) truncated protein product are indicated. BRCrepeats that are still encoded by the predicted transcript are indicated. EL: embryonic lethality day. functions besides the involvement in the maintenance of defect (Hakem et al., 1996; Liu et al., 1996; Ludwig et al., genetic stability. Thus, apart from DNA repair, func- 1997; Suzuki et al., 1997). This striking observation tions have been described for BRCA1 in all phases of introduced a paradox in the biology of BRCA1 and the cell cycle (Deng, 2006), transcription (Lane, 2004) BRCA2. Whereas BRCA-deficient tumor cells proliferate and DNA decatenation (Lou et al., 2005). Studies with the rapidly in situ, cells in developing Brca-deficient embryos Brca1 mouse mutants – or primary cells derived thereof – suffer from a proliferation defect. Although this paradox have revealed several distinct activities of Brca1, including is still unresolved, part of it might be explained by its potential roles in the G2–M cell cycle and spindle the genetic interactions between BRCA1/2 and the p53 assembly checkpoints (Xu et al., 1999b; Wang et al., pathway. Growth-arrested Brca1- and Brca2-deficient 2004a), maintenance of telomere integrity (McPherson embryos showed activation of the Cdkn1a gene encoding et al., 2006) and transcriptional repression of unsynapsed the cyclin-dependent kinase (cdk) inhibitor p21, a p53 chromosomal regions during meiosis (Turner et al., 2004). downstream target known to function in the G1–S cell Interesting with respect to the gender specificity observed cycle checkpoint (Hakem et al., 1996; Suzuki et al., 1997). in BRCA-associated cancers is the reported role for To investigate the role of p53 and p21 in Brca-associated BRCA1 in
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