BRCA1 mutation carriers have an 85% lifetime risk of breast cancer and 60% for ovarian cancer. BRCA1 facilitates DNA double-strand break repair, and dysfunction of BRCA1 leads to hypersensitivity to DNA damaging agents and consequently genomic instability of cells. In this communication, we have examined the tumor incidence and survival of Brca1 heterozygous female mice. Brca1 heterozygotes appear to have a shortened life span with 70% tumor incidence. Lymphoma, but not ovarian and mammary gland tumors, occurs commonly in these mice. After a whole-body exposure to ionizing radiation, Brca1 heterozygous mice have a 3–5-fold higher incidence specific to ovarian tumors, but not lymphoma, when compared with the Brca1+/+ mice. All the tumors from heterozygous mice examined retain the wild-type allele and the cancer cells express Brca1 protein, precluding the chromosomal mechanism for loss of heterozygosity of Brca1 locus. Although the manifestation of BRCA1 haploinsufficiency may be different between human and mouse, this study suggests that women carrying Brca1 mutations may be more prone to ovarian tumor formation after IR exposure than nonmutation carriers.
Women in Western countries have about a 10% lifetime risk of breast cancer, 5–10% of which are familial. Mutations in the breast cancer susceptibility gene BRCA1 account for up to half the hereditary breast cancer cases and almost all the hereditary breast and ovarian cancer cases (Miki et al., 1994; Couch et al., 1997). BRCA1 mutation carriers have a lifetime risk of breast cancer up to 85% and ovarian cancer as high as 60% (Easton et al., 1995). Moreover, a reduced BRCA1 expression is frequently observed in sporadic breast cancer and correlated with the accelerated progression and growth (Thompson et al., 1995).
BRCA1 mediates DNA damage repair, cell-cycle checkpoint control and transcriptional regulation, serving as a tumor suppressor to maintain the global genomic stability. The BRCA1 gene is located on chromosome 17q21 and 100 kb in length, encoding a 220 kDa nuclear phosphoprotein of 1863 amino acids (Miki et al., 1994) characterized by distinctive protein–protein interaction surfaces. The N-terminal RING finger domain dimerizes with BARD1 for ubiquitin ligase activity (Hashizume et al., 2001), while the C-terminus possesses two tandem copies of the BRCT motif that interact with RNA polymerase II holoenzyme (Scully et al., 1997), histone deacetylases (Yarden and Brody, 1999), CBP/p300 (Pao et al., 2000), and CtIP (Li et al., 1999), serving as a phosphopeptide binding module for protein targeting (Yu et al., 2003). Finally, the central region, mainly encoded by exon 11, possesses two nuclear localization signals and interacts with a DNA damage repair complex RAD50/MRE11/NBS1 (Zhong et al., 1999) and transcription repressor ZBRK1 (Zheng et al., 2000b). In response to DNA damage, BRCA1 becomes phosphorylated by ATM (S1387, S1423 and S1524), ATR (S1423) and Chk2 (S988) and translocates to the site of lesion (Zhang et al., 2004). BRCA1 facilitates DNA double-strand break (DSB) repair by homologous recombination via RAD51 and nonhomologous end-joining via RAD50/MRE11/NBS1 complex (Ting and Lee, 2004). In addition, BRCA1 controls cell-cycle checkpoint by regulating the transcription of p21 and GADD45 genes through interaction with CtIP at the C-terminal BRCT domain (Li et al., 1999, 2001).
BRCA1 deficiency renders cells sensitive to ionizing radiation (IR) and DNA cross-linkers and perturbs the genomic stability manifested as aberrant chromosomal integrity and increased mutation rate (Shen et al., 1998). Human tumor cells lacking BRCA1 and mouse embryonic Brca1−/− fibroblasts are highly sensitive to IR (Shen et al., 1998; Foray et al., 1999). However, the effect of BRCA1 haploinsufficiency on the sensitivity to genotoxic agents in peripheral lymphocytes appears controversial. It was reported that the BRCA1+/− peripheral lymphocytes are sensitive to irradiation and have an increased frequency of micronuclei, which can serve as a screening tool for Brca1 mutation carriers (Rothfuss et al., 2000). Subsequent studies failed to confirm such a finding (Baria et al., 2001; Baeyens et al., 2004; Kotsopoulos et al., 2007). Using chromosomal rearrangements to evaluate the sensitivity to genotoxic stress, a significantly higher level of chromosomal damage in the BRCA1+/− lymphocytes compared with normal controls was found after irradiation (Kote-Jarai et al., 2006). On the other hand, Baeyens et al. (2004) found that there is no significant difference in the frequency of chromosomal breakages between breast cancer patients with and without a BRCA1 mutation. Thus, whether BRCA1 heterozygosity has any effect on IR sensitivity remains uncertain. Although the reason causing this discrepancy is unclear, one possibility is that the lymphocytes may not be of a specific cell type exhibiting BRCA1 haploinsufficiency. Therefore, whether haploinsufficiency of BRCA1 manifests in animals is of interest.
In this communication, we examined tumor incidence and survival of Brca1 heterozygous female mice and found that Brca1 heterozygotes had a shortened life span with 70% tumor incidence. These mice commonly succumbed to lymphoma, but neither ovarian nor mammary gland tumors. Upon ionizing irradiation, Brca1 heterozygous mice had a 3–5-fold higher incidence of ovarian tumor, while the incidence of lymphoma did not change. The tumors produced in heterozygous mice retained the wild-type allele and expressed Brca1 protein. This study implicates that women carrying BRCA1 mutations may shorten their life spans and be prone to ovarian tumor upon IR.
Results and discussion
Up to 5% of breast cancer patients have inherited a germline mutation of Brca1 gene, which confers a 50–87% risk of breast cancer. In a general practice, earlier screening for breast cancer by routine mammography is recommended for Brca1 mutation carriers (Brekelmans et al., 2001). In a general population, regular mammographic screening combined with appropriate and prompt treatment can reduce mortality from breast cancer by 30% in women aged 50–59 years and by 14–18% in women aged 40–49 (Fletcher et al., 1993). Besides, therapeutic irradiation is frequently used in treatment of breast and ovarian cancers. As cumulative studies substantiate that BRCA1 is required for radiation-induced DNA damage repair (Ting and Lee, 2004), women with defective BRCA1 genes should have an increased sensitivity to radiation, raising a question about the prudence of medical irradiation for these subjects (Friedenson, 2000).
To approach this question, we compared the effect of irradiation on the survival and tumorigenesis in Brca1-proficient and Brca1 heterozygous female virgin mice. Ninety Brca1+/− female mice were divided into three groups. Each group received a single dose of whole-body irradiation, 0, 2.5 or 5 Gy, at the age of 5–6 weeks. Two groups of 30 Brca1+/+ (wild-type) female mice that received 0 and 5 Gy of whole-body irradiation respectively served as control. The mice were monitored until a moribund state. Without irradiation, Brca1+/− mice have a shorter life span than Brca1+/+ mice with a borderline statistical significance (medium survival days: 713±146 vs 772±102, P=0.037; log-rank test: P=0.07) (Table 1) (Figure 1). The survivals of both groups were reduced significantly by ionizing irradiation in a dose-dependent manner (Figure 1) (Table 1). However, the irradiated Brca1 heterozygous mice did not have a shorter life span than the IR-treated wild-type mice. This may be due to the high dose of gamma irradiation (5 Gy) used in the experiment that masked the underlying genetic difference.
Systemic pathological examinations were performed after sacrifice. Without irradiation, Brca1+/− mice had a 70% tumor incidence; 50% of them developed malignant lymphoma. Only two mice harbored fibroadenoma in mammary gland and two mice developed ovarian tumors. This tumor incidence in Brca1+/− mice was even higher than that of the irradiated Brca1+/+ mice (Table 1). Consistently, only 10% tumor incidence was observed in wild-type mice with a similar but not completely identical genetic background during their life span (Salim et al., 2003). This result suggests that Brca1+/− mice are prone to spontaneous tumor formation. In irradiated Brca1 +/− mice, the tumor incidence increased up to 96.4%. Various types of tumors with different cellular origins were found, including malignant lymphomas, ovary tumors (granulosa cell tumors, cystadenomas and adenocarcinomas), pulmonary adenocarcinomas and hepatocellular carcinomas (Figure 2A) (Table 2). The incidence of malignant lymphoma did not vary among groups of Brca1+/− mice with and without irradiation. After 5.0 Gy irradiation, 57.6% of Brca1+/+ mice developed mainly lymphomas. Most importantly, after a whole-body exposure to IR, Brca1 heterozygous mice had a 3–5 fold higher incidence of ovarian tumors, but not lymphomas, when compared with the Brca1+/+ mice (Table 2). One possible explanation for this observation is that deficiency of Brca1 under IR exposure affects ovary more severely than other cell types. Ovarian epithelial cells may harbor certain properties that help accumulate a higher level of DNA damage and genomic instability upon IR irradiation. For example, ovulatory cycle requires cellular proliferation to repair the ovarian surface after ovulation, allowing proliferation-associated DNA damage to occur (Schildkraut et al., 1997). In general population, ovary is not a common site of IR-induced cancer. The highly increased risk of ovarian tumor formation in Brca1+/− mice suggests that haploinsufficiency of Brca1 has a specific effect on ovarian cells, instead of lymphocytes, consistent with the clinical observation that Brca1 is an organ-specific tumor suppressor.
To determine whether there was a loss of heterozygosity (LOH) of Brca1, 10 tumors from Brca1 heterozygous mice were microdissected and the genotypes were determined by polymerase chain reaction (PCR). As shown in Figure 2B, all Brca1+/− tumors retained the wild-type alleles. The expression of Brca1 was confirmed in all ovarian tumors and 10 other tumors from each group by immunohistochemistry (Figure 2Ca and b), indicating that haploinsufficiency, rather than biallelic inactivation, is the mechanism for the development of tumors in Brca1 heterozygous mice. However, breast tumors developed in women carrying a BRCA1 mutation frequently lose the wild-type allele (Neuhausen and Marshall, 1994). The reason of this discrepancy is not known. Nevertheless, haploinsufficiency of BRCA1 was observed in BRCA1+/− fibroblats in that they are impaired in DNA end-joining activity (Baldeyron et al., 2002) and sensitive to IR (Rothfuss et al., 2000). Thus, it is likely that the impaired DNA repair activity in Brca1 heterozygous cells may in part account for the tumorigenesis in mice.
Breast tumors derived from BRCA1 mutation carriers are frequently associated with p53 mutations (Greenblatt et al., 2001). To test whether abnormality of p53 is associated with tumors derived from IR-irradiated Brca1+/− mice, we examined the expression of p53 in all ovarian tumors and 10 other tumors. These tumors were all negative for p53 staining (Figure 2Cc and d), indicating that p53 stabilization caused by point mutation or other mechanisms is not present in these tumors.
A low incidence of breast cancer, in contrast with a high incidence of ovarian cancer, in our mouse model is intriguing because BRCA1 mutation carriers in human have up to 85% lifetime risk of breast cancer (Easton et al., 1995), and homozygous Brca1 knockout in mouse mammary epithelia frequently produces breast tumor (Deng and Xu, 2004). It is possible that inactivation of a given tumor suppressor results in different types of tumors between human and mice. The best example was revealed in the retinoblastoma gene case in that inactivation of RB causes retinoblastoma in human, but pituitary melanotroph tumor in mice (Nikitin and Lee, 1996).
Without irradiation, Brca1 heterozygous mice have a shorter life span than the wild-type mice. This shortening of life span cannot be explained by the high incidence of lymphoma because the life span of mice carrying tumors is similar to those without tumors (Table 1). Recent studies demonstrate that DNA damage repair proteins play an essential role in life-span determination, as a number of mouse mutants carrying targeted disruption of genes involving in DNA damage repair exhibit premature aging (Vogel et al., 1999; de Boer et al., 2002). Brca1−/− p53+/− mice were also reported to have a decreased life span and showed a phenotype of premature aging (Cao et al., 2003) even in the absence of tumor formation.
Cumulative evidence points out that BRCA1 is essential for several cellular activities including DNA DSB repair (Zheng et al., 2000a; Ting and Lee, 2004). Therefore, women with BRCA1 mutations will be likely to be defective in repairing irradiation-induced DNA damage (Foray et al., 1999), allowing DNA mutations to accumulate more rapidly than nonmutation carriers. Such a pathogenic effect of BRCA1 deficiency is demonstrated by the development of breast cancer at a younger age. The median age for diagnosis of BRCA1-associated breast tumors is 39.5 in contrast with over the age 50 in 80% of sporadic cases (Wagner et al., 1998). In a general practice, women carrying BRCA1 mutations are advised to take annual or semiannual mammography beginning by age 25 (Burke et al., 1997). Since IR is a risk factor of breast cancer (Goss and Sierra, 1998), and our data implies that BRCA1 carriers may be more susceptible to IR-induced tumor, a safety concern on repeated screening mammography for Brca1 carriers is raised. Recently, several large-scale studies concluded that screening mammography is not associated with a significantly increased risk of cancer formation in Brca1 carriers (Goldfrank et al., 2006; Narod et al., 2006). Hence, a small dose of radiation used for diagnostic purpose may not contribute substantially to the burden of breast cancer in BRCA1 mutation carriers.
The risk of therapeutic irradiation for the secondary tumor formation in Brca1 carriers is more obscure. Most radiotherapy protocols use a higher radiation dose than those used in our study. Germline BRCA1 mutation carriers indeed exhibit a higher recurrence rate of another primary tumor in the contralateral breast (Verhoog et al., 1998; Haffty et al., 2002) and ovary (Metcalfe et al., 2005); however, this is more likely due to the underlying genetic defect than the DNA damage by previous regimens. A recent report demonstrated that late toxicity is not increased in 37 Brca1 mutation carriers undergoing breast radiotherapy after a medium follow-up of 6.75 years (Shanley et al., 2006). Since the case number is small and radiation-induced cancers often have a long latency (Kirova et al., 2005), a large-scale epidemiological study should be done to clarify this issue.
Given the differences of the phenotypes of Brca1 heterozygous mutation in mice and human, the results derived from this study may not be directly applicable to human. However, this study demonstrates a possible increase in cancer risk following radiation; therefore, a close follow-up of the development of secondary cancer should be taken into account during management of BRCA1 mutation carriers.
Materials and methods
Animal experiments were performed under federal guidelines and approved by the Institutional Animal Care and Use Committee at UCI. To generate Brca1 heterozygous mice, a partial deletion (amino acids 300–361) of mouse Brca1 gene exon 11 was introduced into the genome of embryonic stem cells by homologous recombination as previously described (Liu et al., 1996). The knockout mice were generated in the 129O1a strain, and backcrossed extensively into the C57BL/6J genetic background. The experimental group consists of 90 Brca1+/− female mice divided into three groups. Each group received a single dose of whole-body irradiation, 0, 2.5 or 5 Gy, at the age of 5–6 weeks. Two groups of 30 Brca1+/+ (wild-type) female mice that received 0 and 5 Gy of whole-body irradiation, respectively, served as control.
Histology and immunohistochemistry
Mice were killed at moribund state, and collected tissues were fixed in 4% paraformaldehyde and processed through paraffin embedding following standard procedures. Sections were stained with Mayer's hematoxylin and eosin (H&E) for histopathological examination. Immunohistochemical staining was performed following the protocol described in a Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA, USA). For antigen retrieval, slides were heated for 10 min in 10 mM citric buffer (pH 6.0) in a microwave oven. The antibodies used were CD45R/B220 (1:100) for B-cell lineage (BD Biosciences, San Diego, CA, USA), CD3 (1:50) for T-cell lineage (rabbit polyclonal, DakoCytomation, Carpinteria, CA, USA), p53 (1:100) (DO1; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and a mouse polyclonal antiserum raised against amino acid residues 1400–1812 of mouse Brca1 (1:100). Two human breast cancers with p53 mutations served as positive controls for p53. A breast cancer derived from a Brca1−/−p53−/− mouse served as negative control for BRCA1.
PCR analysis on LOH
Paraformaldehyde-fixed, paraffin-embedded tumors were sectioned and stained with H&E. The tumor cells were retrieved from slide by laser capture microdissection for analysis of the allelic change of Brca1. PCR was performed for 40 cycles with a pTC-100 thermal controller (MJ Research Inc., Miami, FL, USA) under the following reaction condition: denaturing temperature at 94°C for 30 s, annealing temperature at 65°C for 1 min and elongation temperature at 72°C for 1 min. To detect the mutant allele with targeted deletion of exon 11, a 236 bp product was obtained using a sense oligonucleotide, 5′-IndexTermTGATATTGCTGAAGAGCTTGGCGGC-3′ and an antisense oligonucleotide, 5′-IndexTermTGGGAGTGGCACCTTCCAGGGTCAA-3′, within the pgkneopA cassette. To detect the wild-type allele, a 150-bp product was obtained using a sense oligonucleotide, 5′-IndexTermAACAGCCTGGCATAGCAGTGAGCCA-3′, and antisense oligonucleotide, 5′-IndexTermTTGCGGGTGAGTCCACTTCTCTCTA-3′ within exon 11 of Brca1.
The analyses were performed using StatCalc for Windows software (EpiInfo Version 3.3.2, Centers for Disease Control and Prevention, Atlanta, GA, USA). Tumor incidence according to pathological diagnosis was compared among the four groups by χ2 test. Survival analysis was performed by the Kaplan–Meier method. Statistical significance was assessed using Student's t-test and log-rank sum test. A value of P<0.05 was considered statistically significant.
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We thank Chi-Fen Chen and Xiaoqin Lin for their kind assistance. This work was supported by a grant from the National Institute of Health (RO1 94170) to W-H Lee, a predoctoral fellowship from the Department of Defense (W81XWH-05-1-0322 to SF), and a physician scientist award from the National Health Research Institute in Taiwan to Y-M J.
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Jeng, Y., Cai-Ng, S., Li, A. et al. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 26, 6160–6166 (2007) doi:10.1038/sj.onc.1210451
- heterozygous mutant
- ionizing radiation
- ovarian tumor
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