A Novel BRCA2-Binding Protein and Breast and Ovarian Tumorigenesis
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《新英格兰医药杂志》
A fundamental question of cancer genetics is how genes responsible for inherited cancer contribute to the far more frequent cases of cancer that are purely somatic in origin. Somatic mutations in p53 in a vast range of tumors are similar to inherited germ-line mutations in the p53 tumor-suppressor gene in families with the Li–Fraumeni syndrome and were discovered at about the same time. But the roles of other inherited cancer genes in somatic tumorigenesis have been more difficult to define. Biochemistry has come to the rescue of genetics in this effort. Binding partners of the proteins encoded by cancer genes have been identified, and their interactions have been characterized in vitro, in tumor-cell lines, and in primary tumors.1,2 Hughes-Davies and colleagues3 have identified a protein that binds BRCA2 and have begun to characterize the interaction between these proteins that could lead to tumorigenesis. The protein was named EMSY after the sister — who is a breast-cancer nurse — of one of the authors.
Germ-line mutations in BRCA1 and BRCA2 are responsible for an inherited predisposition to breast and ovarian cancer, but the role of these genes in the development of noninherited cases of breast and ovarian cancer, which are far more common, has been difficult to pin down. On the one hand, BRCA1 and BRCA2 virtually never undergo somatic mutation of the sort frequently found in the p53 gene in many solid tumors. On the other hand, the expression of BRCA1 or BRCA2 protein is reduced in most sporadic breast and ovarian cancers. The mechanisms responsible for this loss of expression probably include somatic deletion of one complete genomic copy of BRCA1 or BRCA2, as revealed by genomic analyses of sporadic breast and ovarian tumors. In a small fraction of sporadic breast tumors, the remaining copy of BRCA1 may be modified by hypermethylation, leading to virtually complete loss of expression of BRCA1. But so far, there is no evidence to suggest that BRCA2 is hypermethylated. How, then, is the expression of BRCA2 lost in sporadic breast and ovarian cancer?
Through their discovery and characterization of a nuclear protein that binds BRCA2, Hughes-Davies et al.3 suggest a means. BRCA2, like BRCA1, is critical to the normal recombinational repair of breaks in double-stranded DNA, the remodeling of chromatin, and the regulation of transcription. Abrogations of these functions are hallmarks of tumor development. After irradiation of cells, EMSY localizes with BRCA2 to chromosomal sites of DNA damage and interacts with proteins involved in the regulation of chromatin. Of most relevance, EMSY binds to the part of BRCA2 that is responsible for transcriptional activation4; an excess of EMSY silences this critical function of BRCA2.
Because an excess of EMSY represses a critical function of BRCA2, one might expect EMSY to be overexpressed in breast and ovarian tumors. Sometimes this is, indeed, the case; the authors found that the EMSY gene was amplified by a factor of more than 1.5 in 13 percent of sporadic breast cancers (70 of 551), 14 percent of melanomas (1 of 7), and 17 percent of high-grade ovarian carcinomas (62 of 360), but not in borderline or low-grade ovarian tumors. EMSY was rarely amplified in other cancers. Genomic amplification of EMSY was associated with high levels of EMSY messenger RNA in cancer-cell lines.
For patients with node-negative breast cancer, amplification of EMSY in tumor tissue was associated with a worse outcome. EMSY amplification was detected in 14 percent of patients with node-positive cancer (48 of 333) and 10 percent of patients with node-negative cancer (13 of 127) with the use of fluorescence in situ hybridization. Median disease-specific survival among patients who had node-negative breast cancer with amplification of EMSY was only 6.4 years, as compared with 14 years among patients who had node-negative breast cancer with normal diploid copies of EMSY (P<0.001). In node-negative tumors, the amplification of EMSY was associated with larger tumors, estrogen-receptor negativity, and amplification of the cyclin D1 gene, which lies near EMSY on chromosome 11q13 and is amplified with EMSY in many tumors. Amplification of EMSY was associated with a poor prognosis after adjustment for the effect of these other markers of unfavorable outcome. (Tumor grade was not included in the analysis.)
Major questions remain about EMSY, BRCA2, and breast and ovarian cancer. Most important, it is not yet known whether EMSY is an oncogene for breast and ovarian cancer — that is, although EMSY represses transcriptional activation of BRCA2, is the overexpression of EMSY sufficient to drive tumorigenesis? More generally, what are the biologic effects of the overexpression of EMSY? Does such overexpression alter DNA repair, chromatin remodeling, or transcriptional regulation? Is the amplification of EMSY associated with the level of expression of BRCA2 in primary breast or ovarian cancers? If the overexpression of EMSY silences critical functions of BRCA2, it might be a surrogate for the loss of BRCA2. Would the overexpression of EMSY be irrelevant in patients with inherited BRCA2 mutations and therefore with breast tumors completely lacking BRCA2? Or would overexpression of EMSY lead to a worse outcome for these patients? It will be fascinating to learn whether the overexpression of EMSY has the same consequences as the loss of BRCA2.
In the meantime, in addition to cyclin D1, MYC, and HER2, we have now identified another protein whose overexpression is associated with aggressive breast and ovarian cancers. It is too early to speculate whether overexpressed EMSY would be a reasonable drug target. On the other hand, amplification of EMSY may prove a useful prognostic marker. Among the group of patients with node-negative breast cancer and a generally good prognosis is a small population of patients with far more severe disease. If in future studies, the amplification of EMSY is verified as a prognostic marker that is independent of tumor characteristics currently in clinical use, then it may well improve our ability to identify high-risk patients with node-negative cancer at an early point in treatment.
Source Information
From the Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle.
References
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000;14:927-939.
Dong Y, Hakimi MA, Chen X, et al. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 2003;12:1087-1099.
Hughes-Davies L, Huntsman D, Ruas M, et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 2003;115:523-535.
Milner J, Ponder B, Hughes-Davies L, Seltmann M, Kouzarides T. Transcriptional activation functions in BRCA2. Nature 1997;386:772-773.(Mary-Claire King, Ph.D.)
Germ-line mutations in BRCA1 and BRCA2 are responsible for an inherited predisposition to breast and ovarian cancer, but the role of these genes in the development of noninherited cases of breast and ovarian cancer, which are far more common, has been difficult to pin down. On the one hand, BRCA1 and BRCA2 virtually never undergo somatic mutation of the sort frequently found in the p53 gene in many solid tumors. On the other hand, the expression of BRCA1 or BRCA2 protein is reduced in most sporadic breast and ovarian cancers. The mechanisms responsible for this loss of expression probably include somatic deletion of one complete genomic copy of BRCA1 or BRCA2, as revealed by genomic analyses of sporadic breast and ovarian tumors. In a small fraction of sporadic breast tumors, the remaining copy of BRCA1 may be modified by hypermethylation, leading to virtually complete loss of expression of BRCA1. But so far, there is no evidence to suggest that BRCA2 is hypermethylated. How, then, is the expression of BRCA2 lost in sporadic breast and ovarian cancer?
Through their discovery and characterization of a nuclear protein that binds BRCA2, Hughes-Davies et al.3 suggest a means. BRCA2, like BRCA1, is critical to the normal recombinational repair of breaks in double-stranded DNA, the remodeling of chromatin, and the regulation of transcription. Abrogations of these functions are hallmarks of tumor development. After irradiation of cells, EMSY localizes with BRCA2 to chromosomal sites of DNA damage and interacts with proteins involved in the regulation of chromatin. Of most relevance, EMSY binds to the part of BRCA2 that is responsible for transcriptional activation4; an excess of EMSY silences this critical function of BRCA2.
Because an excess of EMSY represses a critical function of BRCA2, one might expect EMSY to be overexpressed in breast and ovarian tumors. Sometimes this is, indeed, the case; the authors found that the EMSY gene was amplified by a factor of more than 1.5 in 13 percent of sporadic breast cancers (70 of 551), 14 percent of melanomas (1 of 7), and 17 percent of high-grade ovarian carcinomas (62 of 360), but not in borderline or low-grade ovarian tumors. EMSY was rarely amplified in other cancers. Genomic amplification of EMSY was associated with high levels of EMSY messenger RNA in cancer-cell lines.
For patients with node-negative breast cancer, amplification of EMSY in tumor tissue was associated with a worse outcome. EMSY amplification was detected in 14 percent of patients with node-positive cancer (48 of 333) and 10 percent of patients with node-negative cancer (13 of 127) with the use of fluorescence in situ hybridization. Median disease-specific survival among patients who had node-negative breast cancer with amplification of EMSY was only 6.4 years, as compared with 14 years among patients who had node-negative breast cancer with normal diploid copies of EMSY (P<0.001). In node-negative tumors, the amplification of EMSY was associated with larger tumors, estrogen-receptor negativity, and amplification of the cyclin D1 gene, which lies near EMSY on chromosome 11q13 and is amplified with EMSY in many tumors. Amplification of EMSY was associated with a poor prognosis after adjustment for the effect of these other markers of unfavorable outcome. (Tumor grade was not included in the analysis.)
Major questions remain about EMSY, BRCA2, and breast and ovarian cancer. Most important, it is not yet known whether EMSY is an oncogene for breast and ovarian cancer — that is, although EMSY represses transcriptional activation of BRCA2, is the overexpression of EMSY sufficient to drive tumorigenesis? More generally, what are the biologic effects of the overexpression of EMSY? Does such overexpression alter DNA repair, chromatin remodeling, or transcriptional regulation? Is the amplification of EMSY associated with the level of expression of BRCA2 in primary breast or ovarian cancers? If the overexpression of EMSY silences critical functions of BRCA2, it might be a surrogate for the loss of BRCA2. Would the overexpression of EMSY be irrelevant in patients with inherited BRCA2 mutations and therefore with breast tumors completely lacking BRCA2? Or would overexpression of EMSY lead to a worse outcome for these patients? It will be fascinating to learn whether the overexpression of EMSY has the same consequences as the loss of BRCA2.
In the meantime, in addition to cyclin D1, MYC, and HER2, we have now identified another protein whose overexpression is associated with aggressive breast and ovarian cancers. It is too early to speculate whether overexpressed EMSY would be a reasonable drug target. On the other hand, amplification of EMSY may prove a useful prognostic marker. Among the group of patients with node-negative breast cancer and a generally good prognosis is a small population of patients with far more severe disease. If in future studies, the amplification of EMSY is verified as a prognostic marker that is independent of tumor characteristics currently in clinical use, then it may well improve our ability to identify high-risk patients with node-negative cancer at an early point in treatment.
Source Information
From the Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle.
References
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000;14:927-939.
Dong Y, Hakimi MA, Chen X, et al. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 2003;12:1087-1099.
Hughes-Davies L, Huntsman D, Ruas M, et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 2003;115:523-535.
Milner J, Ponder B, Hughes-Davies L, Seltmann M, Kouzarides T. Transcriptional activation functions in BRCA2. Nature 1997;386:772-773.(Mary-Claire King, Ph.D.)