Human Molecular Genetics, 2001, Vol. 10, No. 7 705-713
© 2001 Oxford University Press
BRCA1 and BRCA2 and the genetics of breast and ovarian cancer
Departments of Medicine and Genetics, Box 357720, University of Washington, Seattle, WA 98195-7720, USA
Received 19 January 2001; Revised and Accepted 29 January 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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Identification of BRCA1 and BRCA2 has led to major changes in the treatment of women with inherited predisposition to breast and ovarian cancer. The innovative feature of these clinical changes has been the genetic approach to identification of high-risk women. The medical and surgical options offered to high-risk women remain conventional. Ultimately, one hopes that understanding the pathways in which BRCA1 and BRCA2 participate in normal breast cells and in breast tumorigenesis will become the basis of non-invasive intervention for women at risk. Understanding the normal functions and regulation of BRCA1 and BRCA2 may reveal how direct or indirect functional inactivation of BRCA genes ultimately leads to breast tumorigenesis. It is now clear that the normal protein products of BRCA1 and BRCA2 are involved in the fundamental cellular processes of maintaining genomic integrity and transcriptional regulation. However, two questions central to cancer genetics remain mysteries. First, why do mutations in ubiquitously expressed genes, which participate in universal pathways, lead specifically to breast and ovarian cancer? Second, does loss of BRCA1 or BRCA2 expression play a role in breast and ovarian cancer generally, beyond the existence of families with inherited mutations in these genes? In this review, we present a model that may explain these paradoxes of BRCA biology.
Together, mutations in BRCA1 and BRCA2 account for the great majority of families with hereditary susceptibility to breast and ovarian cancer (1–4). Other rare breast cancer predisposing genes are discussed in an accompanying review (Nathanson and Weber, this issue pp. 715–720). Tumorigenesis in individuals with germline BRCA mutations requires somatic inactivation of the remaining wild-type allele, suggesting that the BRCA genes are tumor suppressors (5,6). The breast and ovarian cancer phenotypes associated with mutations in BRCA1 and BRCA2 are similar. Although still controversial, very recent genetic epidemiologic studies indicate that BRCA1 mutation carriers have a lifetime risk of breast cancer that is greater than 80% (7). The ultimate lifetime breast cancer risk for BRCA2 mutation carriers approaches that of BRCA1 carriers; however, a later age of disease onset has been documented for BRCA2 mutation carriers (8). In addition to breast cancer, women with BRCA1 mutations have an increased risk of ovarian cancer and, to a much lesser extent, males have an increased risk of prostatic cancer (9). BRCA2 mutation carriers are at increased risk of breast cancer in males and females, and of ovarian, prostatic, pancreatic, gall bladder, bile duct and stomach cancers and melanoma (10). The parallels in BRCA1 and BRCA2 phenotypes suggest a commonality of function.
Biochemical, genetic and cytological studies have revealed multiple functions for BRCA1 and BRCA2. Many of the proteins with which BRCA1 and BRCA2 interact have been identified (reviewed in refs 11–13) (Table 1). BRCA1 and BRCA2 proteins are involved in control of homologous recombination (HR) and double-strand break repair in response to DNA damage (reviewed in refs 14–17). Since these reviews appeared, a role for BRCA1 in the early cellular response to DNA damage has been described. Within minutes of DNA damage, the histone H2A family member H2AX becomes extensively phosphorylated and forms foci at break sites (18). BRCA1 is recruited to these foci several hours before other factors such as RAD50 or RAD51. This suggests that H2AX and BRCA1 initiate repair by modifying local chromatin structure, thereby allowing DNA repair proteins access to the damaged site. In support of an early role for BRCA1 in response to DNA damage is the recent report demonstrating that the BRCT domains of BRCA1 bind double-stranded breaks in DNA (19).
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BRCA1 and BRCA2 also function as transcriptional co-regulators through direct interaction with sequence-specific transcription factors and with components of the transcriptional machinery (reviewed in ref. 20). In addition, chromatin remodeling functions have been attributed to both BRCA1 and BRCA2 (reviewed in refs 12,13). In support of this role for BRCA1, new data suggest that BRCA1 is a component of the human SWI/SNF-related chromatin-remodeling complex (21). Surprisingly, these experiments revealed that the BRCA1-SWI/SNF complex is the predominant BRCA1-containing complex in the cell. Furthermore, BRCA1’s ability to co-activate endogenous p53-dependent stimulation of p21 and p53 promoters is dependent on its physical association with the SWI/SNF complex. It remains to be determined whether the function of BRCA1 in the SWI/SNF complex is to direct chromatin remodeling to sites of DNA damage, allowing repair proteins to function, and/or whether this complex is essential for activation of genes critical to the DNA damage response pathway. BRCA1 and BRCA2 may also regulate transcription of genes involved in other cellular functions (22). Less is known about these gene targets.
Cells that lack BRCA1 or BRCA2 accumulate chromosomal abnormalities including chromosomal breaks, severe aneuploidy and centrosome amplification (reviewed in ref. 23). Chromosomal instability as a result of BRCA1 or BRCA2 deficiency may be the pathogenic basis for breast tumor formation. In women who inherit an inactivating mutation, BRCA deficiency is critical to development of disease and is the result of both the inherited inactivating allele and somatic genomic loss of the wild-type allele in breast or ovarian epithelial cells. We propose that somatic loss of either BRCA1 or BRCA2 is a very common cellular event in both mutant and wild-type BRCA1 and BRCA2 individuals and is a direct result of the distinctive genomic context of the genes themselves. Among sporadic breast and ovarian tumors, 50–70% have lost an allele of BRCA1 and 30–50% have lost an allele of BRCA2 (24,25). These observations suggest that somatic loss of BRCA genes may be associated with sporadic breast and ovarian tumorigenesis, despite a virtually complete absence of somatic point mutations in the BRCA genes. In addition, reduction or complete loss of BRCA1and BRCA2 message and protein has been documented in the majority of sporadic breast and ovarian tumors evaluated (26,27). As we suggest below, genetic inactivation of BRCA1 or BRCA2 may frequently be a rate-limiting step in development of sporadic disease.
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DISTINCTIVE GENOMIC INSTABILITY OF BRCA GENES |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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The genomic regions of both BRCA1 and BRCA2 contain very high densities of repetitive DNA elements that may contribute to genetic instability (Fig. 1). The BRCA1 region consists of 42% Alu sequences and 5% non-Alu repeats (28). The BRCA2 genomic region is 47% repetitive DNA, consisting of 20% Alu sequences and 27% LINE and MER repetitive DNA. Genes that contain such a high density of repetitive DNA are rare. Alu-dense regions of the genome are associated with a high density of genes and localize predominantly to R bands of metaphase chromosomes, which are involved in homologous and non-homologous chromosomal exchange (reviewed in refs 29,30). Numerous disease-associated genetic rearrangements, mediated by Alu sequences, have been described. Given the density of repeat elements in BRCA1 and BRCA2, it is not surprising that Alu-mediated genomic rearrangements within BRCA1 and genomic rearrangement in BRCA2 have been observed (31,32). It is likely that careful analysis of BRCA1 and BRCA2 in as-yet unexplained high-risk breast cancer families will reveal other such complex rearrangements (T.D. Walsh, unpublished results).
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The eukaryotic genome is compacted in the nucleus of a cell so that faithful and ordered DNA replication occurs during each cell cycle. Chromatin is organized into topologically constrained loops that are anchored to the matrix by matrix attachment regions (MARs) (reviewed in refs 33–35). Sequencing of fragments that attach chromatin loops to the underlying nuclear matrix revealed that most matrix attachment regions are transcribed with attachment correlated with transcriptional activity (36). In addition, 30% of these sequences contained Alu-repeats. These features are characteristic of the BRCA genes.
One mechanism that may contribute to the generation of large deletions observed in and around the BRCA1 and BRCA2 genes in both inherited and sporadic tumors is shown in Figure 2. Deletion of a chromatin loop containing all or a large portion of BRCA1 or BRCA2 may be mediated by HR between repeat sequences. These sequences may be far apart on linear DNA but physically close in the nucleus, perhaps due to their anchorage to the nuclear matrix. For example, if during replication a chromosome were to break near a replication fork, it may be incorrectly repaired by HR to a replication fork at a nearby anchorage point, resulting in deletion of the intervening DNA.
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ESTROGENS AND SURVIVAL OF BRCA-DEFICIENT CELLS |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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Generally, failure of DNA repair leads to growth arrest or cell death. BRCA-deficient mice die early in embryogenesis as the result of these cellular responses. In cells of women who inherit BRCA-inactivating mutations, loss of the wild-type allele would be expected to virtually always result in cell cycle arrest and, if DNA damage was not successfully repaired, in apoptosis. Descendents of these cells would never be observed. The first paradox of BRCA biology is that BRCA-deficient breast or ovarian epithelial cells develop tumors, instead of undergoing cell death. What is unique to breast and ovarian epithelial cells that allows them to escape apoptosis in response to the loss of DNA repair capacity that is associated with abrogation of BRCA1 or BRCA2 function? It is tempting to speculate that estrogen is the missing link.
Reproductive factors linked to estrogen production are associated with breast cancer risk. The longer a woman is exposed to estrogen either endogenously or exogenously, the higher her risk of developing breast cancer; both early onset of menarche and late menopause are associated with increased risk. How do BRCA1 and BRCA2 fit into this picture? BRCA1 and BRCA2 expression is developmentally regulated. Their expression is upregulated during puberty and pregnancy, when estrogen levels are dramatically increased. This suggests that estrogen might stimulate expression of BRCA1 and/or BRCA2.
Human breast tissue begins to develop very early, usually during the sixth week of fetal development. Fetal breast tissue is responsive to circulating maternal hormones. After early infancy, no developmental changes occur in the breast until puberty. During puberty, in response to a dramatic surge in estrogen production, the breast epithelial cells rapidly proliferate. Unlike the cells of other rapidly proliferating epithelia such as intestine or uterine endometrium, the progeny of this proliferative burst are retained in the breast epithelium. Breast lobules are clonal. Indeed, an entire functioning mammary gland may develop from a single cell (37).
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INHERITED BREAST CANCER |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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A model for breast tumorigenesis among women with inherited BRCA mutations is illustrated in Figure 3. All breast epithelial cells of a BRCA mutation carrier have one inactivated allele of BRCA1 or BRCA2. During puberty, in direct response to estrogen surges, these cells rapidly proliferate. It is likely that this dramatic increase in the rate of cellular replication strains the DNA repair capacity of breast epithelial cells. Somatic genomic alterations involving the repeat elements of BRCA1 or BRCA2 will occur at high frequency. The large deletions observed by loss of heterozygosity (LOH) analysis of BRCA1 and BRCA2 tumors reflect these alterations, possibly driven by the mechanism described in Figure 2.
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Most cells that have both inherited and somatic inactivating mutations of BRCA1 or BRCA2 will be unable to repair DNA damage sustained in the following cell cycle and will die. However, in the rapidly proliferating breast epithelium, some repair-deficient cells may escape death, at least briefly. Because these BRCA-null cells are deficient in repair, they would sustain DNA damage at many sites, often including genes essential to cell cycle checkpoint activation. Mutation of a checkpoint gene would enable a BRCA-null cell to escape death permanently and to proliferate. As Figure 3 suggests, genetic instability caused by loss of BRCA1 or BRCA2 may enable additional mutation, including mutation in checkpoint genes.
For BRCA1-mediated tumorigenesis, one of the key checkpoint genes is p53. Evidence from conditional knock-out mice suggests that loss of BRCA1 in mammary cells leads to incomplete proliferation, apoptosis and tumors at a low frequency (38). In these mice, additional heterozygous mutation in p53 leads to many more mammary tumors, most of which have lost the remaining p53 allele. Tumors in patients with germline BRCA1 or BRCA2 mutations are frequently associated with somatic mutations of p53. In the proposed model, mutant p53 would inactivate a cell cycle checkpoint and lead instead to uncontrolled proliferation and invasive growth. Cells that have successfully escaped death by checkpoint will probably accumulate multiple mutations. Recent reports reveal that amplification of the MYB oncogene (the human homolog of the avian myeloblastosis viral oncogene) (39) and reduction of the anti-apoptotic gene Bcl-2 (40), are characteristic of most breast tumors from BRCA1 mutation carriers.
If somatic inactivation of the wild-type BRCA allele and mutation of critical checkpoint genes occur during puberty, then breast tumorigenesis would be an early event in the lives of these women (Fig. 3). On the other hand, some BRCA mutation carriers develop disease much later or not at all. In these women it is likely that all cells somatically inactivated for BRCA1 or BRCA2 succumb to checkpoint-mediated death.
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SPORADIC BREAST CANCER |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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A possible role of BRCA1 and BRCA2 in sporadic tumorigenesis is also summarized in Figure 3. As in inherited disease, estrogen-mediated proliferation of breast and ovarian epithelial cells and the distinctive genomic context of the BRCA genes are critical components of this pathway. During puberty, estrogen stimulates breast epithelial cells to proliferate. Among somatic alterations that appear in these rapidly dividing cells, alterations of BRCA1 or BRCA2 are likely to be relatively frequent because of the density of repeats in these genes. Inactivation of the second allele in such a cell would generally result in cell death. Tumorigenesis would require inactivation of both alleles in a cell capable of escaping cell cycle checkpoints. Unlike inherited disease, inactivation of genes critical to cell cycle checkpoints could occur prior to inactivation of the second BRCA allele. However, these events must occur in the same cell. Therefore, BRCA-mediated sporadic tumorigenesis would be less likely. Also, because more mutational events are required, tumors occur later in a woman’s life.
Various genetic mechanisms may be responsible for somatic inactivation of both alleles of BRCA1 or BRCA2. One possibility is that the same mechanism may be responsible for somatic genomic inactivation of both alleles, albeit not simultaneously. Traditional LOH analyses have been interpreted as loss of only one allele of the target gene. However, careful analysis of sporadic tumors may suggest that either one or two alleles can be lost, yielding similar patterns of allelic imbalance. As Figure 2 indicates, repeat-mediated loss of chromatin loops formed at different points in the cell cycle will yield deletions of different sizes. If this process occurs in both copies of the BRCA1 region or the BRCA2 region, deletions including the BRCA gene will overlap but not be identical. If genomic deletions overlap, they may incorrectly appear to define one region of LOH. To determine whether this is a mechanism for BRCA inactivation, it would be useful to carry out a detailed analysis in a series of breast tumors using gene-specific single nucleotide polymorphisms (SNPs) for whom the phase can be determined.
Alternatively, it has been proposed that inactivation of one BRCA allele could result in an overall decrease in BRCA function (haplo-insufficiency). Presence of only one BRCA1 or BRCA2 allele is clearly sufficient for normal growth and development, because persons heterozygous for BRCA mutations have normal phenotypes apart from their cancer predisposition. However, under conditions of cellular stress in breast or ovarian epithelium, caused by estrogen-stimulated proliferation, it is possible that even a modest decrease in BRCA function in cells with one somatically inactivated allele could increase the risk of additional cancer promoting mutations. It is not known whether inactivation of one BRCA allele, in an otherwise normal breast epithelial cell, results in any decrease in cellular message and/or protein. It is possible that the remaining allele compensates by increasing its gene expression. A test of haplo-insufficiency in breast epithelial cells would involve careful evaluation of BRCA message and protein levels in cells containing one inactivated and one wild-type gene compared to wild-type BRCA cells. It would be useful to determine whether BRCA expression is influenced to the same degree by estrogen in wild-type versus heterozygous-deficient breast epithelial cells.
Third, transcriptional silencing may inactivate BRCA alleles. BRCA alleles may be functionally inactivated by loss of proteins that positively regulate their expression or by an increase in negative regulatory proteins. Determining how BRCA genes are regulated is critical to determining whether indirect functional inactivation ultimately leads to BRCA-mediated sporadic tumorigenesis. Table 2 indicates known regulatory proteins of BRCA1 and BRCA2 and, if regulation is direct, the nucleotide sites at which they function. BRCA1 expression is regulated at several regions within the BRCA1 promoter by various cellular factors. The recent identification of Id4 (inhibitor of DNA binding 4) as a negative regulator of BRCA1 expression is of particular interest. Id4 inversely regulates BRCA1 expression (41). Overexpression of Id4 (and concomitant reduction of BRCA1 expression) is associated with anchorage-independent growth, a critical characteristic of tumor cells. The relationship between Id4 and BRCA1 may be important for breast cancer because estrogen reduces Id4 expression, hence increasing expression of BRCA1. Conversely, breast epithelial cells that are no longer responsive to estrogen may overexpress Id4, with consequent reduction in BRCA1 expression. If this occurs in a cell that has lost one BRCA allele through somatic inactivation, then these cells would be BRCA deficient. Id4, and regulatory proteins with similar effects, may be therapeutic targets, in that BRCA1 expression in breast epithelial cells could be maintained by constraining expression of negative regulators.
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Thus far, only one protein has been identified as a regulator of BRCA2 expression. This is NF-
B, which upregulates BRCA2 transcription by binding the BRCA2 promoter (42). NF-B regulates expression of a number of genes with critical roles in apoptosis, tumorigenesis and inflammation. NF-B stimulates cell cycle progression in ER– (estrogen-receptor negative) breast cancer cells (43). This pathway may be important to proliferation in a subset of sporadic breast tumors which overexpress BRCA2 (44). This connection could resolve the apparent paradox of absence of BRCA2 expression in some sporadic breast tumors, but overexpression of BRCA2 in others. Transcriptional silencing of one BRCA allele could also be accomplished through methylation of CpG islands, which are often found in the regulatory regions of genes. The 5' regulatory region of the BRCA1 gene contains a TATA-less promoter with a high cytosine-guanine content, making BRCA1 an excellent candidate for CpG methylation. In a small subset (5–10%) of sporadic breast tumors, BRCA1 transcription is silenced by the methylation of CpG residues, reflected in the absence of protein expression (T.D. Walsh, unpublished data). In a recent report, the BRCA1 promoter was methylated in 15% (12 of 81) of sporadic ovarian tumors (45). Methylation as a mechanism for gene inactivation may occur in some BRCA1 tumors, but not in BRCA2 tumors. The BRCA2 promoter does not appear to be methylated in normal tissues or in breast or ovarian tumors (46).
Finally, BRCA1 and BRCA2 might be inactivated post-translationally by failure of phosphorylation or other post-translational modifications. Post-translational modification by phosphorylation is required for normal BRCA1 and BRCA2 function. Some of the proteins which phosphorylate BRCA1 or BRCA2 have been identified (Table 3). Of these, the roles of ATM, ATR and Chk2 in phosphorylating BRCA1 in response to DNA damage are likely to be most critical to carcinogenesis. Whereas it has been known for some time that BRCA1 is regulated by phosphorylation, it now appears that BRCA2 is phosphorylated as well. The C-terminus of BRCA2 is phosphorylated by hBUBR1, a mitotic checkpoint gene (47). In addition the activation domain of BRCA2 has recently been shown to possess a binding site for a kinase (48). It is not yet clear how phosphorylation of BRCA2 is critical to its function.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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How does loss of BRCA1 or BRCA2 function lead to breast or ovarian cancer? Furthermore, why do genes which are ubiquitously expressed and participate in universal cellular pathways lead, when mutant, specifically (or almost specifically) to breast and ovarian cancer? We suggest that understanding of the distinctive genomic contexts of the BRCA genes, coupled with the biology of breast development, is required to solve this biological puzzle. The existence of critical windows of vulnerability to breast tumorigenesis during female development is consistent with this model. Rapid proliferation of breast epithelial cells during puberty and pregnancy offer the ideal opportunity for somatic mutation, including loss of a BRCA1 or BRCA2 allele. In this context, it is noteworthy that somatic mutation of BRCA1 or BRCA2 is similar (i.e. it is virtually always loss of a large genomic region), whether the loss involves the remaining wild-type allele in a BRCA1 or BRCA2 tumor or the somatic loss of BRCA1 or BRCA2 in sporadic breast cancer.
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ACKNOWLEDGEMENTS |
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We thank Drs Ming K. Lee, Kelly N. Owens and Chris Gunter for preparing figures for this manuscript. This work was supported by NIH grant CA27632. M.-C.K. is an American Cancer Society Research Professor.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 206 616 4294; Fax: +1 206 616 4295; Email: piri@u.washington.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONDISTINCTIVE GENOMIC INSTABILITY...ESTROGENS AND SURVIVAL OF...INHERITED BREAST CANCERSPORADIC BREAST CANCERSUMMARYREFERENCES |
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 B. A. Nexo, U. Vogel, A. Olsen, T. Ketelsen, Z. Bukowy, B. L. Thomsen, H. Wallin, K. Overvad, and A. Tjonneland A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55 Carcinogenesis, May 1, 2003; 24(5): 899 - 904. [Abstract] [Full Text] [PDF]
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M. A. Fleming, J. D. Potter, C. J. Ramirez, G. K. Ostrander, and E. A. Ostrander Understanding missense mutations in the BRCA1 gene: An evolutionary approach PNAS, February 4, 2003; 100(3): 1151 - 1156. [Abstract] [Full Text] [PDF]
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Y. Liu, D. M. Virshup, R. L. White, and L.-C. Hsu Regulation of BRCA1 Phosphorylation by Interaction with Protein Phosphatase 1{alpha} Cancer Res., November 15, 2002; 62(22): 6357 - 6361. [Abstract] [Full Text] [PDF]
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S Gad, M Klinger, V Caux-Moncoutier, S Pages-Berhouet, M Gauthier-Villars, I Coupier, A Bensimon, A Aurias, and D Stoppa-Lyonnet Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families J. Med. Genet., November 1, 2002; 39(11): 817 - 821. [Full Text] [PDF]
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 F. Bertucci, F. Eisinger, R. Tagett, H. Sobol, and D. Birnbaum Re: Gene Expression Profiles of BRCA1-Linked, BRCA2-Linked, and Sporadic Ovarian Cancers J Natl Cancer Inst, October 2, 2002; 94(19): 1506 - 1507. [Full Text] [PDF]
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C. M. Wong, J. M. F. Lee, T. C. M. Lau, S. T. Fan, and I. O. L. Ng Clinicopathological Significance of Loss of Heterozygosity on Chromosome 13q in Hepatocellular Carcinoma Clin. Cancer Res., July 1, 2002; 8(7): 2266 - 2272. [Abstract] [Full Text] [PDF]
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G. Chenevix-Trench, T. Dork, C. Scott, and J. Hopper RESPONSE: Re: Dominant Negative ATM Mutations in Breast Cancer Families J Natl Cancer Inst, June 19, 2002; 94(12): 952 - 952. [Full Text] [PDF]
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 Y.-F. Hu and R. Li JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction Genes & Dev., June 15, 2002; 16(12): 1509 - 1517. [Abstract] [Full Text] [PDF]
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Z. Gu, R. Y. Lee, T. C. Skaar, K. B. Bouker, J. N. Welch, J. Lu, A. Liu, Y. Zhu, N. Davis, F. Leonessa, et al. Association of Interferon Regulatory Factor-1, Nucleophosmin, Nuclear Factor-{kappa}B, and Cyclic AMP Response Element Binding with Acquired Resistance to Faslodex (ICI 182,780) Cancer Res., June 1, 2002; 62(12): 3428 - 3437. [Abstract] [Full Text] [PDF]
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K. Sobczak and W. J. Krzyzosiak Structural Determinants of BRCA1 Translational Regulation J. Biol. Chem., May 3, 2002; 277(19): 17349 - 17358. [Abstract] [Full Text] [PDF]
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D. Thompson and D. Easton Variation in BRCA1 Cancer Risks by Mutation Position Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 329 - 336. [Abstract] [Full Text] [PDF]
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N. Hu, G. Li, W.-J. Li, C. Wang, A. M. Goldstein, Z.-Z. Tang, M. J. Roth, S. M. Dawsey, J. Huang, Q.-H. Wang, et al. Infrequent Mutation in the BRCA2 Gene in Esophageal Squamous Cell Carcinoma Clin. Cancer Res., April 1, 2002; 8(4): 1121 - 1126. [Abstract] [Full Text] [PDF]
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 M.-C. King, S. Wieand, K. Hale, M. Lee, T. Walsh, K. Owens, J. Tait, L. Ford, B. K. Dunn, J. Costantino, et al. Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial JAMA, November 14, 2001; 286(18): 2251 - 2256. [Abstract] [Full Text] [PDF]
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 C. Hanks Genetic Technologies and Women: The Importance of Context Inmaculada de Melo-Martin St. Mary's University Bulletin of Science Technology Society, October 1, 2001; 21(5): 354 - 360. [Abstract] [PDF]
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