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Onc19 8REV 2..2 Oncogene (2000) 19, 1059 ± 1064 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation Chu-Xia Deng*,1 and Frank Scott1 1Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA Germline mutations in the tumor suppressor BRCA1 The BRCA1 gene contains 24 exons, which encode a predispose women to breast and ovarian cancers. Current large protein of 1863 amino acids in humans and 1812 evidence demonstrates that mutations in BRCA1 do not amino acids in mice (Bennett et al., 1995; Lane et al., directly result in tumor formation, but instead cause 1995; Marquis et al., 1995; Miki et al., 1994). It also genetic instability, subjecting cells to high risks of contains a number of motifs that may have distinct malignant transformation. In an animal model in which functions [reviewed in (Paterson, 1998), and Figure 1]. Brca1 is mutated speci®cally in mammary epithelium, The zinc ®nger domain in the amino terminus interacts tumorigenesis occurs in mutant glands at low frequency with DNA directly or indirectly through protein ± after a long latency. Notably, introduction of a p53-null protein interactions (Jin et al., 1997; Wu et al., 1996). allele signi®cantly enhanced mammary gland tumor The carboxyl terminus contains a BRCT domain, formation in Brca1 conditional mutant mice. These which is a relatively common feature of proteins results are consistent with a model that Brca1 is a involved in DNA damage response checkpoints (Bork caretaker gene, whose absence causes genetic instability et al., 1997). The BRCT domain interacts with p53 and and triggers further alterations, including inactivation of functions as a transactivator in both p53 dependent tumor suppressor genes and/or activation of oncogenes, and independent fashions (Chai et al., 1999; Chapman leading to tumor formation. Oncogene (2000) 19, 1059 ± and Verma, 1996; Ouchi et al., 1998; Zhang et al., 1064. 1998). Some of the known downstream target genes of BRCA1 include p21 (Somasundaram et al., 1997), ER Keywords: Brca1; p53; centrosome; G2-M checkpoint; (Fan et al., 1999) and Gadd45 (Harkin et al., 1999). tumorigenesis Exon 11 of the BRCA1 gene constitutes over 60% of the protein and encodes two putative nuclear localiza- tion signals (Chen et al., 1996a,b). It also contains a domain that interacts with RAD51, a homolog of E. Introduction Coli RecA involved in DNA damage repair (Scully et al., 1997a,b; Shinohara et al., 1992). Breast cancer is the most common cancer and the In the past 4 years, at least ®ve groups have second leading cause of cancer mortality in women, disrupted Brca1 in the mouse using gene targeting with approximately one in nine being aected over (Gowen et al., 1996; Hakem et al., 1996; Liu et al., their lifetime. An estimated 175 000 women will be 1996; Ludwig et al., 1997; Shen et al., 1998). Embryos diagnosed with breast cancer this year, and approxi- homozygous for these mutations exhibited phenotypic mately 43 000 will die. About 5 ± 10% of breast cancers variations and died between embryonic days (E)5.5 ± are heritable, which may be caused by mutations of 13.5 (Table 1), displaying severe developmental delay tumor suppressor genes (reviewed in Alberg and and cellular defects. Although the molecular basis for Helzlsouer, 1997; Brody and Biesecker, 1998; Ellisen the phenotypic variations is not well understood, it has and Haber, 1998; Paterson, 1998). The ®rst gene found been shown that the Brca1 locus exhibits a complex to be associated with increased susceptibility to familial pattern of RNA splicing since its initial cloning (Cui et breast and ovarian cancer is BRCA1, which was al., 1998a,b; Lu et al., 1996; Miki et al., 1994; Thakur mapped in 1990 (Hall et al., 1990) and was et al., 1997; Wilson et al., 1997; Xu et al., 1995). It has subsequently cloned 4 years later (Miki et al., 1994). been demonstrated recently that alternative splicing of Germline mutations in BRCA1 have been detected in Brca1 exon 11 generates two major transcripts, a approximately 90% of familial breast/ovarian cancers 7.2 kb full length transcripts and a 3.9 kb D-exon 11 and about 50% of familial cases with breast cancer transcripts (Figure 1 and Xu et al., 1999b). Thus, it is alone (reviewed in Alberg and Helzlsouer, 1997; conceivable that residual activities of undisrupted Paterson, 1998). Despite strong evidence to support splicing variants could partially compensate for the the view that BRCA1 is a tumor suppressor in humans, loss of the full length Brca1 transcripts, resulting in the the precise mechanism through which BRCA1 muta- extended survival of mutant embryos. Indeed, a recent tions cause tumor formation is not clear. report showed that embryonic stem cells homozygous for a targeted disruption of Brca1 exon 11 (Gowen et al., 1996) did contain the D-exon 11 transcripts (Cressman et al., 1999). Nonetheless, the proliferation defects associated with the targeted disruption of Brca1 seem incompatible with the tumor suppressor function *Correspondence: C-X Deng assigned to this gene and raise questions about the BRCA1 and tumorigenesis C-X Deng and F Scott 1060 mechanism by which BRCA1 mutations cause tumor- reagents (Scully et al., 1997b). RAD51 is involved in igenesis. Moreover, in contrast to humans hetero- ATP-dependent DNA strand exchange reactions and is zygous for BRCA1 mutations, who have a greatly known to be a homolog of yeast RecA, which increased risk for breast cancer, the heterozygous mice functions in homologous recombination and DNA for the targeted mutations are tumor free. Apparently, damage repair (Ogawa et al., 1993). More evidence the early lethality associated with the loss of Brca1 in connecting Brca1 to DNA damage repair comes from the mouse obscures functions of this gene in later two recent ®ndings. The ®rst study used cultured stages of mammalian development, cell cycle regula- embryonic stem cells and demonstrated that Brca1- tion, and especially in tumor suppression. de®cient cells were hypersensitive to oxidative reagents, Much of our understanding of Brca1 functions including g-irradiation and hydrogen peroxide, and comes from several recent studies analysing cultured were defective in transcription-coupled repair (Gowen cells which lack Brca1, in addition to a speci®cally et al., 1998). Studying blastocysts and embryos, Shen et engineered mouse, which carries a Brca1 mutation that al. (1998) found that Brca1-de®cient embryos were not is speci®cally introduced into mammary epithelial cells only hypersensitive to g-irradiation but also displayed (Gowen et al., 1998; Hagmann, 1999; Shen et al., 1998; numerical and structural chromosomal aberrations, Xu et al., 1999a,b). These studies uncovered multiple which may be a direct consequence of unrepaired roles for Brca1 in DNA damage repair, G2-M and DNA damage. centrosome checkpoints, and mammary gland tumor Notably, embryos carrying a targeted disruption of formation. The present review will focus on these Rad51 or Brca2, another tumor suppressor involved in recent ®ndings regarding Brca1 functions in genetic breast tumor formation (Tavtigian et al., 1996; stability and tumorigenesis. Wooster et al., 1995), exhibited similar phenotypes to the Brca1 ± null embryos. They were all hypersensitive to g-irradiation and displayed chromosomal abnorm- BRCA1 and DNA damage repair alities, and exhibited early embryonic lethality, which Increasing evidence suggests that BRCA1 is involved in could be partially rescued by a p53 mutation (Lim and DNA damage repair. The ®rst hint of such a function Hasty, 1996; Ludwig et al., 1997; Patel et al., 1998; of BRCA1 came from observations that BRCA1 Sharan et al., 1997; Shen et al., 1998). These striking colocalizes with RAD51 (Scully et al., 1997a), and is similarities of RAD51, BRCA1, and BRCA2 mutants relocated to intranuclear structures where DNA suggested a functional link between BRCA1 and replicates after treatment with DNA damaging BRCA2 in the RAD51-mediated DNA damage repair process. Disruption in any one of these genes impairs the function of the proposed BRCA1/BRCA2/RAD51 complex (Brugarolas and Jacks, 1997; Chen et al., 1998) and leads to genetic instability. Brca1 and cell cycle checkpoints Ample evidence suggests that BRCA1 is involved in cell cycle control, which monitors the physical integrity of DNA and coordinates cell cycle transitions (reviewed in Morgan and Kastan, 1997; Weinert, 1998). It has been shown that BRCA1 is associated with many cell cycle proteins, including E2F, cdc2 and Figure 1 Structure of Brca1 and its major functional domains. cyclins (Wang et al., 1997). BRCA1 levels vary at Brca1 contains 24 exons (black boxes), which encode several dierent phases of the cell cycle. The protein become major functional domains (as indicated). Alternative splicing of Brca1 exon 11 generates two major transcripts, i.e. the full length hyperphosphorylated during late G1 and S phases, and (7.2 kb) and the D-exon 11 (3.9 kb) transcripts is transiently dephosphorylated early after M phase Table 1 Brca1 mutations and phenotypes Phenotypes of homozygous embryos/mammary Mutations of Brca1 glands Authors Deletion of exons 5 and 6 Die between E6-7, proliferation defects Hakem et al. (1996) Deletion of exon 2 Similar to above Ludwig et al. (1997) Deletion of 184 bp within 5' portion of Similar to above Liu et al. (1996) exon 11 Deletion of 330 bp of intron 10 and Die between E8.5 ± 13.5, neuroepithelial Gowen et al. (1996) 1.5 kb of exon 11 abnormalities Deletion of 330 bp of intron 10 and 440 Die at E8, growth retardation, hypersensitive to Shen et al. (1998) bp of exon 11 g-irradiation, chromosomal abnormalities Cre-mediated deletion of exon 11 in Blunted ductal development of mammary Xu et al.
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