National Cancer Institute®
Last Modified: January 1, 2002
UI - 11447881
AU - Van den Ouweland AM
TI - [From gene to disease; from BRCA1 OR BRCA2 to breast cancer]
SO - Ned Tijdschr Geneeskd 2001 Jun 23;145(25):1228
UI - 11499181
AU - Memarzadeh S; Berek JS
TI - Advances in the management of epithelial ovarian cancer.
SO - J Reprod Med 2001 Jul;46(7):621-9; discussion 629-30
AD - Division of Gynecologic Oncology, University of California-Los Angeles School of Medicine, 27-136 CNS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1740, USA.
More than 23,400 new cases of ovarian cancer and 13,900 deaths are expected in the United States this year. Epithelial ovarian cancer is the most common histologic type of ovarian malignancy. Although there have been advances in the chemotherapeutic treatment of ovarian cancer, the five year survival of women with advanced-stage disease is 25-30%. Because the disease is typically asymptomatic until the disease has metastasized and because effective screening strategies are not unavailable, 70-75% of women present with advanced-stage disease. Of ovarian cancer cases, 90-95% are sporadic and 5-10% associated with germ-line mutations, including BRCA1 and BRCA2. Known risk factors for ovarian cancer include nulliparity and a strong family history of ovarian cancer. The use of oral contraceptives is known to decrease the risk of ovarian cancer: five years of use will decrease the risk by 50%. The staging of ovarian cancer (according to the International Federation of Obstetrics and Gynecology) requires surgical exploration. Determining the extent of disease is essential to appropriate management. Survival in patients with metastatic disease is improved in those who undergo optimal primary cytoreductive surgery. Adjuvant chemotherapy is recommended in patients with high-risk, early-stage disease and all patients with advanced-stage disease. Standard chemotherapy is a combination of paclitaxel and carboplatin. Selected patients with recurrent disease can undergo secondary cytoreductive surgery. Second-line chemotherapy for patients who initially respond to paclitaxel and carboplatin and who have a prolonged disease progression-free intervals (longer than 12 months) can be re-treated with either drug or both. Those whose responses to initial therapy were less successful can be treated with other chemotherapeutic agents--e.g., liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.
UI - 11554927
AU - Ibe S; Fujita K; Toyomoto T; Shimazaki N; Kaneko R; Tanabe A; Takebe I;
TI - Kuroda S; Kobayashi T; Toji S; Tamai K; Yamamoto H; Koiwai O Terminal deoxynucleotidyltransferase is negatively regulated by direct interaction with proliferating cell nuclear antigen.
SO - Genes Cells 2001 Sep;6(9):815-24
AD - Faculty of Science and Technology, Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba 278-8510, Japan.
BACKGROUND: The repertoires of Ig and TcR are generated by a combinatorial rearrangement of variable (V), diversity (D), and joining (J) segments (V(D)J recombination) in B- and T-cells. Terminal deoxynucleotidyltransferase (TdT) adds extra nucleotides (N nucleotides) at the junctions of the gene segments to enhance the Ig and TcR genes diversity. Using an anti-TdT antibody column, TdT has been purified as a member of a megadalton protein complex from rat thymus. The N region would be synthesized with the large protein complex. RESULTS: The cDNAs for proliferating cell nuclear antigen (PCNA) were isolated by yeast two-hybrid screening as the gene products which directly interacted with TdT. The interaction between PCNA and TdT was confirmed by co-immunoprecipitation, both in vitro and in vivo. TdT binds directly to a PCNA trimer, as shown by gel filtration. TdT interacts with PCNA in its DNA polymerization domain (DPD), but not in its BRCA-1 C-terminal (BRCT) domain. TdT activity was reduced to 17% of the maximum value by TdT/PCNA complex formation. CONCLUSION: TdT interacts directly with PCNA through its DPD. A functional consequence of this interaction is the negative regulation of TdT activity. These findings suggest that TdT catalyses the addition of N nucleotides under the negative control of PCNA during V(D)J recombination.
UI - 11583951
AU - Kataoka A; Tada M; Yano M; Furuuchi K; Cornain S; Hamada J; Suzuki G;
TI - Yamada H; Todo S; Moriuchi T Development of a yeast stop codon assay readily and generally applicable to human genes.
SO - Am J Pathol 2001 Oct;159(4):1239-45
AD - First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
We established a yeast-based method to screen chain-terminating mutations that is readily applicable to any gene of interest. Based on the finding that 18- to 24-base-long homologous sequences are sufficient for gap repair in vivo in yeast, we used a strategy to amplify a test-gene fragment with addition of 24-bp sequences homologous to both cut-ends of a yeast expression vector, pMT18. After co-transformation with the amplified fragment and the linearized pMT18, each yeast (Saccharomyces cerevisiae) cell automatically forms a single-copy circular plasmid (because of CEN/ARS), which expresses a test-gene::ADE2 chimera protein. When the reading frame of the test-gene contains a nonsense or frameshift mutation, truncation of the chimera protein results in lack of ADE2 activity, leading to formation of a red colony. By using a nested polymerase chain reaction using proofreading Pfu polymerase to ensure specificity of the product, the assay achieved a low background (false positivity). We applied the assay to BRCA1, APC, hMSH6, and E-cadherin genes, and successfully detected mutations in mRNA and genomic DNA. Because this method--universal stop codon assay--requires only 4 to 5 days to screen a number of samples for any target gene, it may serve as a high-throughput screening system of general utility for chain-terminating mutations that are most prevalent in human genetic diseases.
UI - 11598149
AU - Zweemer RP; Ryan A; Snijders AM; Hermsen MA; Meijer GA; Beller U; Menko
TI - FH; Jacobs IJ; Baak JP; Verheijen RH; Kenemans P; van Diest PJ Comparative genomic hybridization of microdissected familial ovarian carcinoma: two deleted regions on chromosome 15q not previously identified in sporadic ovarian carcinoma.
SO - Lab Invest 2001 Oct;81(10):1363-70
AD - Department of Obstetrics and Gynaecology, VU Medical Center, Amsterdam, The Netherlands. firstname.lastname@example.org
The vast majority of familial ovarian cancers harbor a germline mutation in either the breast cancer gene BRCA1 or BRCA2 tumor suppressor genes. However, mutations of these genes in sporadic ovarian cancer are rare. This suggests that in contrast to hereditary disease, BRCA1 and BRCA2 are not commonly involved in sporadic ovarian cancer and may indicate that there are two distinct pathways for the development of ovarian cancer. To characterize further differences between hereditary and sporadic cancers, the comparative genomic hybridization technique was employed to analyze changes in copy number of genetic material in a panel of 36 microdissected hereditary ovarian cancers. Gains at 8q23-qter (18 of 36, 5 cases with high-level amplifications), 3q26.3-qter (18 of 36, 2 cases with high-level amplifications), 11q22 (11 of 36) and 2q31-32 (8 of 36) were most frequent. Losses most frequently occurred (in decreasing order of frequency) on 8p21-pter (23 of 36), 16q22-pter (19 of 36), 22q13 (19 of 36), 9q31-33 (16 of 36), 12q24 (16 of 36), 15q11-15 (16 of 36), 17p12-13 (14 of 36), Xp21-22 (14 of 36), 20q13 (13 of 36), 15q24-25 (12 of 36), and 18q21 (12 of 36). Comparison with the literature revealed that the majority of these genetic alterations are also common in sporadic ovarian cancer. Deletions of 15q11-15, 15q24-25, 8p21-ter, 22q13, 12q24 and gains at 11q22, 13q22, and 17q23-25, however, appear to be specific to hereditary ovarian cancer. Aberrations at 15q11-15 and 15q24-25 have not yet been described in familial ovarian cancer. In these regions, important tumor suppressor genes, including the hRAD51 gene, are located. These and other yet unknown suppressor genes may be involved in a specific carcinogenic pathway for familial ovarian cancer and may explain the distinct clinical presentation and behavior of familial ovarian cancer.
UI - 11668223
AU - Runnebaum IB; Wang-Gohrke S; Vesprini D; Kreienberg R; Lynch H; Moslehi
TI - R; Ghadirian P; Weber B; Godwin AK; Risch H; Garber J; Lerman C; Olopade OI; Foulkes WD; Karlan B; Warner E; Rosen B; Rebbeck T; Tonin P; Dube MP; Kieback DG; Narod SA Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.
SO - Pharmacogenetics 2001 Oct;11(7):635-8
AD - Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.
UI - 11673680
AU - Brewster A; Helzlsouer K
TI - Breast cancer epidemiology, prevention, and early detection.
SO - Curr Opin Oncol 2001 Nov;13(6):420-5
AD - Department of Medical Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Breast cancer remains a worldwide public health concern despite the fact that mortality rates have been declining in some countries as a result of improvements in adjuvant therapy and screening for breast cancer. In the prevention arena, advances in our understanding of the effects of tamoxifen have led to the investigations of newer agents that may provide extended options for breast cancer prevention in high-risk women. For women who are carriers of a mutation in the breast cancer susceptibility genes BRCA1 or BRCA2, prophylactic oophorectomy and bilateral mastectomy have emerged as preventative surgical options that can significantly impact breast cancer risk. In addition, the identification of potentially modifiable risk factors for breast cancer such as dietary folate intake, alcohol consumption, physical activity, and certain anthropometric factors provides opportunities for intervening in breast cancer prevention both among women at average and high risk. The challenge remains in overcoming the limitations of mammography and clinical breast examination by developing and evaluating new technologies for breast cancer screening such as digital mammogram and breast magnetic resonance imaging.
UI - 11673682
AU - Zellars R; Frassica D
TI - Radiation therapy in the management of breast cancer: an annual review of selected publications.
SO - Curr Opin Oncol 2001 Nov;13(6):431-5
AD - Johns Hopkins Oncology Center, Lutherville, Maryland 21093, USA.
Radiation oncology is essential in the management of breast cancer. Each year the scientific literature is replete with evidence of radiation's role in the treatment of this disease. The goal of this article is to motivate the reader to discuss and critically review some of these publications. The authors have made a subjective selection of clinical publications addressing radiation and breast cancer from the past 13 months. Articles were chosen on the basis of their ability to influence both current and future therapy. Some readers will no doubt disagree with our choices; however, if this disappointment generates discussion and review of these and other articles, we have achieved our goal.
UI - 11688463
AU - Colgan TJ; Murphy J; Cole DE; Narod S; Rosen B
TI - Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status.
SO - Am J Surg Pathol 2001 Oct;25(10):1283-9
AD - Mount Sinai Hospital and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. email@example.com
Prophylactic oophorectomy (PO) is an option for women at increased risk for ovarian carcinoma. In this study the value of intensive pathologic examination of PO specimens and accompanying resected tissues in the identification of occult carcinoma and any association of occult carcinoma with BRCA germline mutation status were ascertained. Specimens from 60 consecutive PO patients, who were not suspected of having any ovarian tumor at the time of surgery, were subjected to standardized, complete pathologic examination in a prospective study over an 8-year period. Extra-ovarian tissues were examined as well, but they were not subject to the same standardized protocol. Any occult carcinoma of the ovaries or fallopian tubes was noted. The BRCA status and follow-up of patients were obtained, if available. Fifty-five of the 60 PO specimens did not show any evidence of malignancy. Of the 32 patients in this group followed for >1 year, all are alive and well. The remaining five patients, all BRCA1 mutation positive, showed occult carcinoma of the ovaries and/or in situ or invasive carcinoma of a fallopian tube. One of these five patients has died of abdominal carcinomatosis; four continue to be well, but follow-up is <4 years in all cases. Occult carcinoma is present in a small proportion of BRCA-positive or unknown PO patients and may be of prognostic significance. The entire ovaries and tubes from PO patients should be submitted for histologic examination to identify malignancy.
UI - 11693810
AU - von Smitten K
TI - Prophylactic breast surgery for women with BRCA1 and BRCA2 germline mutations.
SO - Tumori 2001 Jul-Aug;87(4):S13-5
AD - Breast Surgery Unit, Helsinki University Central Hospital, Hus, Finland. firstname.lastname@example.org
UI - 11704836
AU - Atlas E; Stramwasser M; Mueller CR
TI - A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element.
SO - Oncogene 2001 Oct 25;20(48):7110-4
AD - Cancer Research Laboratories, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Transcriptional regulation of the BRCA1 proximal promoter has been suggested to play a role in the decreased expression of BRCA1 observed in sporadic breast cancer. Computer analysis of the sequence of the proximal promoter reveals the presence of a potential CREB site. We have identified CREB/ATF-1 as the factor interacting with this site in nuclear extracts from MCF-7 and T-47D cells. This site is shown to be important for the constitutive expression of the promoter in these cells, as well as in Hep G2 cells. Despite the presence of this site, the BRCA1 promoter is not responsive to cAMP induction. It appears that CREB acts as a constitutive positive element for BRCA1 expression and that any mechanism inactivating CREB function would have a dramatic effect on BRCA1 expression.
UI - 11712780
AU - Charafe-Jauffre E; Eisinger F; Mathoulin-Portier MP; Sobol H; Jacquemier
TI - J PS2 expression in BRCA1-associated breast cancers.
SO - Anticancer Res 2001 Jul-Aug;21(4B):2877-81
AD - Department de Pathologie Institut Paoli-Calmettes, Marseille, France.
BACKGROUND: PS2-expression is controlled by estrogens and is a prognostic factor for long-term and post-relapse survival. Breast carcinomas associated with a BRCA1 mutation (BRCA1-BC'S) exhibit many specific features, particularly for ER expression. Our purpose was to determine if pS2-expression was different in BRCA1-BC's compared with sporadic breast cancers. MATERIALS AND METHODS: We studied, by immunohistochemistry pS2-cxpression in a series of 33 BRCA1-BC's and a series of 193 sporadic cases according to many parameter including hormone receptors (ER and PR). RESULTS: In BRCA1-BC's, pS2 was expressed in only 10/33 (30.3%) carcinomas, and 4/4 (100%) ER positive: among sporadic carcinomas, 133/193 (68.9%) cases were pS2-positive, 102/127(80.37%) ER positive; the difference was significant (p<0.0001). In univariate analysis, pS2-expression was correlated with many parameters including hormonal receptor status and absence of BRCA1 mutation. In multivariate analysis, pS2-expression was still correlated with ER but no more with BRCA1 mutation. CONCLUSION: pS2-expression in BRCA1-BC's was significantly different from sporadic breast cancer (p<0.0001) and correlated in a multivariate analysis with the same factors in sporadic and BRCA1-BC's but not with BRCA1 mutation.
UI - 11759652
AU - Narod SA; Sun P; Risch HA; Hereditary Ovarian Cancer Clinical Study
TI - Group Ovarian cancer, oral contraceptives, and BRCA mutations.
SO - N Engl J Med 2001 Dec 6;345(23):1706-7
UI - 11733976
AU - Smith SA; Richards WE; Caito K; Hanjani P; Markman M; DeGeest K; Gallion
TI - HH BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: a Gynecologic Oncology Group study.
SO - Gynecol Oncol 2001 Dec;83(3):586-92
AD - Division of Gynecologic Oncology, University of Kentucky, Combs Research Building, Room 124C, 800 Rose Street, Lexington, Kentucky 40536, USA.
OBJECTIVE: The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. METHOD: Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. RESULTS: Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. CONCLUSION: In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing. (c)2001 Elsevier Science.
UI - 11701949
AU - Stec I; van Vliet M; van Eijk R; Meijers H; Kroeze KH; Dauwerse JG; van
TI - Ommen GJ; Cornelisse CJ; den Dunnen JT; Devilee P A partial BRCA1 sequence homology mapping to 4q28.
SO - Cytogenet Cell Genet 2001;94(1-2):26-9
AD - Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. I.Stec@LUMC.nl
Using a BRCA1 cDNA probe in Southern analysis, we detected a sequence of 348 bp on 4q28 that is homologous to the 3' end of BRCA1. A 28-kb sequence contig has been assembled spanning the homologous region, which we designated BRCA1-h. An open reading frame was identified encoding a sequence of 82 amino acids; 22 of the last 23 amino acids are identical to the last 23 residues of BRCA1. BLAST-searches, RT-PCR and RACE-experiments have been unable to provide evidence that BRCA1-h is part of an expressed gene. Copyright 2001 S. Karger AG, Basel
UI - 11685871
AU - Swisher E
TI - Hereditary cancers in obstetrics and gynecology.
SO - Clin Obstet Gynecol 2001 Sep;44(3):450-63
AD - University of Washington, Seattle, Washington, USA. email@example.com
The lack of information regarding the effectiveness of screening strategies, chemoprevention, or surgical prophylaxis, and the uncertainty regarding penetrance and risk modification has led many experts to recommend that genetic testing for BRCA1, BRCA2, and other cancer susceptibility genes be performed only in a research setting. Patients, however, are likely to increasingly request access to genetic testing and deserve up-to-date counseling about recent advancements in our knowledge. The primary care physician should concentrate on identifying women likely to be at high-risk for cancer for further referral, allowing the cancer genetics specialist to track down medical records, clarify the pedigree, discuss genetic testing, and provide access to the appropriate cancer specialist to discuss risk reduction.
UI - 11589066
AU - Coukos G; Rubin SC
TI - Gene therapy for ovarian cancer.
SO - Oncology (Huntingt) 2001 Sep;15(9):1197-204, 1207; discussion 1207-8
AD - Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. GCoukos@mail.obgyn.upenn.edu
Advances in molecular virology and biotechnology have led to the engineering of vectors that can efficiently transfer genes to target cells. Gene therapy strategies were developed along two lines: Cytotoxic approaches involve the transfer of genes that encode enzymes, which convert inactive prodrugs into cytotoxic drugs. Corrective gene therapy approaches aim to repair specific molecular alterations in signal transduction mechanisms that control the cell cycle or induce apoptosis. Clinical evidence suggests that gene therapies are best suited for patients with minimal residual disease. Multimodality approaches with conventional strategies and novel therapeutic tools in various combinations will most likely prove advantageous, compared to single-modality treatments. However, clinical trials will need to test these hypotheses.
UI - 11594337
AU - Hallowell N; Jacobs I; Richards M; Mackay J; Gore M
TI - Surveillance or surgery? A description of the factors that influence high risk premenopausal women's decisions about prophylactic oophorectomy.
SO - J Med Genet 2001 Oct;38(10):683-91
UI - 11719181
AU - Mendell JT; Dietz HC
TI - When the message goes awry: disease-producing mutations that influence mRNA content and performance.
SO - Cell 2001 Nov 16;107(4):411-4
AD - Howard Hughes Medical Institute, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Mutations that cause disease commonly occur in the coding sequence and directly influence protein structure and function. However, many diseases result from mutations that influence various aspects of mRNA metabolism, including processing, export, stability, and translational control.
UI - 11720902
AU - Laud K; Hornez L; Gourdou I; Belair L; Arnold A; Peyrat JP; Djiane J
TI - Expression of BRCA1 gene in ewe mammary epithelial cells during pregnancy: regulation by growth hormone and steroid hormones.
SO - Eur J Endocrinol 2001 Dec;145(6):763-70
AD - Laboratoire de Biologie Cellulaire et Moleculaire, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cedex, France.
OBJECTIVE: Steroid hormones (estradiol and progesterone) in association with prolactin and growth hormone are involved in lobulo alveolar development of the mammary gland during pregnancy. We hypothesized that the BRCA1 gene may be induced by these different hormones. METHODS AND RESULTS: In this study, we have demonstrated by Northern blot and in situ hybridization, that the expression of ovine (o) BRCA1 mRNA in mammary epithelial cells increased dramatically during a short period in the second half of pregnancy (days 70 to 112) and decreased at the end of pregnancy. The increase in oBRCA1 mRNA expression is concomitant with rapid lobulo alveolar growth. Using an in vivo protocol to artificially induce mammary gland development, we demonstrated by the real-time RT-PCR method that growth hormone in association with estrogen, progesterone and hydrocortisone induces an increase of BRCA1 mRNA expression in the ewe mammary gland. Moreover, we showed that estradiol and progesterone induce oBRCA1 expression in primary cultures of ewe mammary gland. CONCLUSIONS: These results suggest that BRCA1 is a potential regulator of the effects of steroid hormones and growth hormone in the induction of mammary epithelial cell proliferation.
UI - 11508855
AU - Dimitrov SD; Matouskova E; Forejt J
TI - Expression of BRCA1, NBR1 and NBR2 genes in human breast cancer cells.
SO - Folia Biol (Praha) 2001;47(4):120-7
AD - Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague.
BRCA1 is a tumour suppressor gene with a caretaker function in the DNA-damage repair and the maintenance of genome integrity. The human BRCA1 and NBR2 genes and the homologous Brcal and Nbr1 mouse genes are situated head-to-head on human chromosome 17q21 and on mouse chromosome 11, respectively. Their transcription start sites, located on opposite DNA strands, are separated by 218 bp in humans, and by 289 bp in mice. Because of this intimate contact and because of our previous observation of a quasi-reciprocal expression pattern of Brca1 and Nbr1 in mouse spermatogenesis, we estimated here the relative mRNA expression of BRCA1, NBR1 (next-to-BRCA1) and NBR2 genes in a panel of permanent cell lines and primary cell cultures derived from human breast cancer or normal mammary tissue. The analysis revealed highly significant downregulation of BRCA1 in 11 out of 12 examined tumour cell lines and primary cell cultures as compared to non-malignant mammary cells. Two isoforms of NBR1(1A) and the classical NBR1(1B) transcripts were found in cells from malignant mammary tissues, all of them downregulated in respect to normal cells. The expression of NBR2 differed, being increased in three permanent tumour cell lines and slightly decreased in all primary breast cancer cell cultures. The in silico analysis revealed two new putative domains of the predicted NBR1 protein, suggesting its role in the ubiquitin pathway. The recent identification of the ubiquitin protein ligase activity of BRCA1 implies a possible functional connection between both genes.
UI - 11794203
AU - Offit K; Robson M; Schrag D
TI - Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1498-9; discussion 1499-500
UI - 11794204
AU - Narod S
TI - Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1498; discussion 1499-500
UI - 11794205
AU - Riggs T
TI - Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1499; discussion 1499-500
UI - 11794206
AU - Stoutjesdijk MJ; Barentsz JO
TI - Prophylactic mastectomy in carriers of BRCA mutations.
SO - N Engl J Med 2001 Nov 15;345(20):1499; discussion 1499-500
UI - 11407860
AU - Kachhap SK; Vetale SP; Dange P; Ghosh SN
TI - Reduced expression of the BRCA1 gene and increased chromosomal instability in MCF-7 cell line.
SO - Cell Biol Int 2001;25(6):547-51
AD - Cell Biology Division, Cancer Research Institute, Tata Memorial Centre, Parel, Mumbai 400012, India.
Using clonal cell cultures, a significant increase in chromosomal aberrations (aneuplolidy, dicentrics and chromatid breaks) were observed in MCF-7 cells compared with HeLa. BRCA1 expression was lower in MCF-7 cells than in HeLa cells. Since BRCA1 is known to play a role in the maintenance of chromosomal integrity, the increase in chromosomal aberrations in MCF-7 clones suggests that downregulation of BRCA1 expression could be one of the possible mechanisms for increased chromosomal instability in this cell line. Copyright 2001 Academic Press.
UI - 11668617
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Lallas TA; Kirby P; Buller RE
TI - Ovarian cancer BRCA1 mutation detection: Protein truncation test (PTT) outperforms single strand conformation polymorphism analysis (SSCP).
SO - Hum Mutat 2001 Oct;18(4):337-44
AD - Division of Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
Recent studies have shown that the BRCA1 tumor suppressor gene plays a role in the development of both hereditary and sporadic ovarian cancer. Since several different mechanisms may give rise to tumor gene defects, a better understanding of these mechanisms may identify BRCA1 as an attractive therapeutic target in ovarian cancer. Sequencing this large gene is not practical on a population-wide basis. The optimal screening strategy is yet to be determined. The purpose of our study is to compare two common screening techniques: the protein truncation test (PTT) and single strand conformational polymorphism analysis (SSCP). Ninety-four patients with epithelial ovarian cancer and available snap-frozen tissue were screened for BRCA1 mutations by both PTT (five individual PCR reactions with complete translation of the product in the TNT System (Promega, Madison, WI)) and SSCP (41 individual PCR reactions covering the entire coding sequence). All abnormal results were confirmed by sequencing. A paired peripheral blood DNA sample was utilized to determine if the sequence abnormality was a germline mutation. Twenty-three mutations in BRCA1 were found in 22 patients (14 germline, eight somatic, one unknown) including four novel mutations: E489X, 3558delT, 3871delGTCT, del exon 7-10. Although the predictive value of a negative test was close for the two methods (PTT 99.1%, SSCP 99.8%), the comparison of positive predictive value overwhelmingly favored PTT (100.0%, vs. 26.4%, respectively). The specificity for PTT was 100.0% while the sensitivity was 82.6%. While for SSCP, the specificity was 99.0% and the sensitivity was only 60.9%. The concordance rate for the two screening tests was 88.9%. Only SSCP can detect missense mutations. PTT is a superior screening test for truncating BRCA1 mutations that are expected to be of clinical significance. Copyright 2001 Wiley-Liss, Inc.
UI - 11781837
AU - Fan S; Yuan R; Ma YX; Meng Q; Goldberg ID; Rosen EM
TI - Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1.
SO - Oncogene 2001 Dec 13;20(57):8215-35
AD - Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.
Unregulated expression of wild-type BRCA1 (wtBRCA1) confers an altered phenotype in cultured human prostate cancer cells, characterized by chemosensitivity, susceptibility to apoptosis, decreased DNA repair activity, and alterations of key cell regulatory proteins. We now report that the expression of truncated or mutant full-length BRCA1 genes can abrogate certain phenotypic characteristics and/or confer the opposite phenotype to the wild-type BRCA1 gene. In particular, several carboxyl-terminal truncated BRCA1 proteins conferred chemoresistance, decreased susceptibility to apoptosis, and decreased ability to suppress in vivo tumor growth. These truncated BRCA1 proteins also blocked the ability of ectopically expressed wtBRCA1 to induce chemosensitivity and to inhibit estrogen receptor transcriptional activity. Studies using epitope-tagged truncated proteins confirmed their expression, nuclear localization, and functionality. On the other hand, in cells with no endogenous wild-type BRCA1 (HCC1937 human breast cancer cells), the wtBRCA1 gene enhanced cellular DNA repair activity and rendered the cells resistant to DNA damage; while truncated BRCA1 proteins blocked the wtBRCA1-induced chemoresistance. Our findings suggest that truncated BRCA1 proteins can inhibit the function of wild-type BRCA1. They raise the possibility that some inherited BRCA1 mutations may actively promote oncogenesis by blocking the function of the remaining wild-type BRCA1 allele, although this hypothesis remains to be proved.
UI - 11737473
AU - Halperin R; Zehavi S; Langer R; Hadas E; Bukovsky I; Schneider D
TI - Primary peritoneal serous papillary carcinoma: a new epidemiologic trend? A matched-case comparison with ovarian serous papillary cancer.
SO - Int J Gynecol Cancer 2001 Sep-Oct;11(5):403-8
AD - Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Zerifin, Israel.
The aim of the study was to examine the prevalence of primary peritoneal serous papillary carcinoma (PPSPC) as compared with ovarian serous papillary cancer (OSPC), and to study the clinicopathologic features and the frequency of germline BRCA1 and BRCA2 mutations in patients with PPSPC compared with those with OSPC. The study group included 28 cases of PPSPC. The comparison group included 35 female patients with OSPC, matched for stage, grade, and histologic subtype. All tumors were staged as either IIIB, IIIC or IV according to FIGO criteria. The patient characteristics, family and personal history of malignancies, the prevalence of germline BRCA mutations, clinicopathologic findings, presenting symptoms, pre- and intraoperative findings, and survival were compared in a matched-case retrospective study comparing patients with PPSPC vs. those with OSPC. Statistical analysis was made using Student's t-test, Chi-square, Wilcoxon, Kaplan-Meier and log-rank methods. Women with PPSPC had a significantly earlier menarche (P = 0.037) and a higher number or births (P = 0.03) than women with OSPC. No difference was found with regard to the prevalence of germline BRCA mutations in women with PPSPC compared with women with OSPC (7.1% vs. 25.7%). There was a significant increase (P = 0.02) in the incidence of abdominal distension as reported by PPSPC (64%) vs. OSPC patients (26%). Significantly more women with PPSPC than with OSPC presented with clinical ascites (P = 0.0001) and without palpable pelvic mass (P = 0.000001). On exploratory laparotomy, significantly more women with PPSPC than with OSPC had a minimal disease in the pelvis (P = 0.0087). Three-year survival analysis demonstrated a significantly worse survival rate for the PPSPC group than for the OSPC group (P = 0.017). A significant increase in the prevalence of PPSPC compared with OSPC was observed during the study years (P = 0.00001). We concluded that PPSPC and OSPC might be two distinct cancers, presenting a new epidemiologic trend regarding the increased incidence of PPSPC.
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