National Cancer Institute®
Last Modified: February 1, 2002
UI - 11719215
AU - Shepherd TG; Kockeritz L; Szrajber MR; Muller WJ; Hassell JA
TI - The pea3 subfamily ets genes are required for HER2/Neu-mediated mammary oncogenesis.
SO - Curr Biol 2001 Nov 13;11(22):1739-48
AD - Institute for Molecular Biology and Biotechnology, McMaster University, 1280 Main Street, Hamilton, Ontario L8S 4K1, Canada.
BACKGROUND: The PEA3 Ets transcription factor is overexpressed in the vast majority of human breast tumors and in nearly all of those of the HER2/Neu-positive subclass. PEA3 is also overexpressed in various transgenic mouse models of this disease. Whether PEA3 plays an essential role in HER2/Neu-mediated oncogenesis has heretofore not been addressed. RESULTS: Here, we report that each of the three highly related ets genes of the pea3 subfamily (pea3, er81, and erm) were coordinately overexpressed in mammary tumors of MMTV-neu transgenic mice. Other ets genes normally expressed in the mammary gland were not upregulated in these tumors. Expression of a dominant-negative pea3 transgene under the control of the MMTV promoter in mammary epithelial cells of MMTV-neu transgenic mice dramatically delayed the onset of mammary tumors and reduced the number and size of such tumors in individual mice. Those tumors that arose in bitransgenic mice expressed the MMTV-neu transgene, but not the MMTV-dominant-negative pea3 transgene. CONCLUSIONS: These findings imply that one or more of the PEA3 subfamily Ets proteins or other Ets proteins with related DNA binding specificity play an essential role in Neu-mediated mammary oncogenesis. Hence, agents that inhibit the expression or activity of the PEA3 subfamily proteins may prove efficacious in the treatment of breast cancer.
UI - 11745672
AU - Boecker W; Buerger H; Schmitz K; Ellis IA; van Diest PJ; Sinn HP;
TI - Geradts J; Diallo R; Poremba C; Herbst H Ductal epithelial proliferations of the breast: a biological continuum? Comparative genomic hybridization and high-molecular-weight cytokeratin expression patterns.
SO - J Pathol 2001 Nov;195(4):415-21
AD - Gerhard-Domagk-Institute of Pathology, University of Munster, Germany. email@example.com
According to current concepts, benign proliferative breast disease (BPBD) is a direct precursor of breast cancer, in a spectrum ranging from ductal hyperplasia to overtly invasive carcinoma. In this study, comparative genomic hybridization (CGH) was used to screen ductal hyperplasia and other BPBD lesions and ductal carcinoma in situ (DCIS) for common genomic abnormalities, to test the relationship between these hyperplastic and neoplastic lesions. Immunohistochemistry for cytokeratin 5/6 was used as a diagnostic adjunct to distinguish ductal hyperplasia from DCIS. A total of 42 cases of BPBD comprising ductal hyperplasia of the usual type (n=14), papilloma (n=22), tubular adenoma (n=3), and adenosis (n=3), as well as 52 cases of DCIS, were studied. All cases of BPBD consistently displayed the presence of a subpopulation of cytokeratin 5/6-expressing basal-type cells within the proliferative lesion, whereas all of the non-high-grade and most of the high-grade DCIS lesions lacked cytokeratin 5/6-positive cells. Whereas gross genomic alterations, as determined by CGH, were undetectable in BPBD, distinct genetic changes characterized all cases of DCIS, with one exception. These results confirm the usefulness of cytokeratin 5/6 immunohistology in the diagnosis of BPBD and neoplastic breast lesions and support the view that BPBD and DCIS are not closely related entities and that BPBD is not an obligate direct precursor of DCIS. Copyright 2001 John Wiley & Sons, Ltd.
UI - 11745673
AU - Bartlett JM; Going JJ; Mallon EA; Watters AD; Reeves JR; Stanton P;
TI - Richmond J; Donald B; Ferrier R; Cooke TG Evaluating HER2 amplification and overexpression in breast cancer.
SO - J Pathol 2001 Nov;195(4):422-8
AD - University Department of Surgery, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK. firstname.lastname@example.org
The development of Herceptin (Trazumatab) makes testing for HER2 status important for choosing optimal therapy in breast cancer. This study addresses the precision, accuracy, and reproducibility of HER2 assays. HER2 was assessed retrospectively by immunohistochemistry (IHC) with Dako 'Herceptest', by IHC with the monoclonal antibody CB11, and by fluorescence in situ hybridization (FISH, PathVysion), in a series of 216 formalin-fixed breast carcinomas including 191 for which quantitative HER2 data from radioimmunohistochemistry (Q-IHC) were available. All tests were scored independently by two observers. Positivity rates varied between Herceptest (12.6%), FISH (19.4%), and CB11 IHC (28.5%). Kappa values showed that IHC-based tests were more susceptible to inter-observer variation (kappa=0.67 and 0.74 for Herceptest and CB11, respectively) than FISH (kappa=0.973). Overall test accuracy (see the Materials and methods section) for CB11 IHC (83.8%) was lower than Herceptest (87.4%) or FISH (93.2%). FISH predicted p185 HER2 overexpression (determined by Q-IHC) better (concordance index C.Ind. 0.90) than CB11 IHC (C.Ind.=0.85) or Herceptest (C.Ind.=0.81). Of 42 cases with gene amplification by FISH, 67% were positive in the Herceptest (2+ or 3+) vs. 83% with CB11. Of 174 cases negative by FISH, 96% were negative in the Herceptest and 68% with CB11. In conclusion, FISH is the most accurate, reproducible, and precise predictor of HER2 overexpression in routine diagnostic laboratories. Copyright 2001 John Wiley & Sons, Ltd.
UI - 11734330
AU - Schwab M; Claas A; Savelyeva L
TI - BRCA2: a genetic risk factor for breast cancer.
SO - Cancer Lett 2002 Jan 10;175(1):1-8
AD - Deutsches Krebsforschungszentrum, Abteilung Zytogenetik H-0400, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany. email@example.com
The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 a few years ago has been greeted with great excitement and has raised hopes that they might illuminate the common mechanisms of this disease. Today we have to recognize that these expectations remain unfulfilled. Mutations in BRCA1 and BRCA2 account only for a relatively small proportion of breast cancers, even within the group of familiar clusters, they seem to be virtually non-existing in sporadic breast cancers. A substantial proportion of familiar breast cancer clusters has failed to provide evidence for an association with mutations in either BRCA1 or BRCA2, thus we have to look forward to the identification of additional breast cancer susceptibility genes. What has been most disappointing is that the mutation status of BRCA1/2 can provide only limited information for cancer risk. Initial assessments had indicated a risk of close to 90% for mutation carriers to develop breast cancer until age 75 - a value that turned out to be restricted to high-risk families in which the BRCA1 and BRCA2 genes had been genomically mapped. In unselected clusters the risk appears much lower, some estimates suggest less than 40%. Both BRCA1 and BRCA2 large encode proteins that appear to have a plethora of functions, with a conspicuous association to DNA repair and DNA recombination, and probably transcription activation. Defects in DNA repair can result in cancer predisposition syndromes and are recognized as being instrumental in cancer progression. Central questions have remained unanswered: What is the function of damaged BRCA1 and BRCA2 genes in breast cancer risk? What is the basis of large variations of risk conferred to the patients by identical mutations? How can the predictive value of mutation surveys be increased?
UI - 11748639
AU - Roylance R; Gorman P; Hanby A; Tomlinson I
TI - Allelic imbalance analysis of chromosome 16q shows that grade I and grade III invasive ductal breast cancers follow different genetic pathways.
SO - J Pathol 2002 Jan;196(1):32-6
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. firstname.lastname@example.org
It remains controversial as to whether low- and high-grade invasive ductal breast cancers are related by progression through grade, or generally follow distinct genetic pathways. It has previously been shown by comparative genomic hybridization (CGH) that the latter is more likely to be correct, based on the high frequency of chromosome 16q deletion in grade I cancers, but not in grade III. This study used microsatellite markers on 16q to confirm the differences between grade I and grade III tumours and to exclude the possibility that grade III tumours generally arise from grade I tumours through a process involving regain of 16q. The concordance between the CGH and microsatellite data is good but imperfect, probably reflecting the different sensitivities and specificities of the two techniques and the varying mechanisms of allele loss in each tumour type. Copyright 2002 John Wiley & Sons, Ltd.
UI - 11521793
AU - Olopade OI; Pichert G
TI - Cancer genetics in oncology practice.
SO - Ann Oncol 2001 Jul;12(7):895-908
AD - University of Chicago Pritzker School of Medicine, Illinois, USA. email@example.com
Cancer is a genetic disease caused by the progressive accumulation of mutations in critical genes that control cell growth and differentiation. Completion of the Human Genome Project promises to revolutionize the practice of Medicine, especially Oncology care. The tremendous gains in the knowledge of the structure and function of human genes will surely impact the diagnosis, prognosis and treatment of cancer. Moreover, it will lead to more effective cancer control through the use of genetics to quantify individual cancer risks. This article reviews the current status of genetic testing and counseling for cancer risk assessment and will suggest a framework for integrating such counseling into oncology practice.
UI - 11774202
AU - Wang SC; Zhang L; Hortobagyi GN; Hung MC
TI - Targeting HER2: recent developments and future directions for breast cancer patients.
SO - Semin Oncol 2001 Dec;28(6 Suppl 18):21-9
AD - Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Road, Houston, TX 77030, USA.
Overexpression of the HER2/neu oncogene (also known as c-erbB2) is a frequent molecular event in multiple human cancers, including breast and ovarian cancer. Patients with cancer that overexpress HER2/neu are associated with unfavorable prognosis, shorter relapse time, and low survival rate. Treatments that target HER2/neu expression in cancer cells have been shown to be useful strategies to significantly reverse the malignancy induced by HER2/neu overexpression. The humanized anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) has proven to be effective in clinical trials in patients with metastatic breast cancer. In addition, tyrosine kinase inhibitors such as emodin can also target the HER2/neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-overexpressing breast cancer cells. Emodin also sensitizes HER2/neu-overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene. We have identified a number of potent transcriptional regulators, including the ets family member PEA3 and the adenovirus type 5 E1A, which are able to repress HER2/neu gene expression. Expression of these transcriptional regulators resulted in downregulation of HER2/neu promoter activity and reversed the transformed phenotype of the cancer cells in vitro. In vivo studies show that these HER2/neu repressors can act therapeutically as tumor suppressor genes for tumors that overexpress HER2/neu. These preclinical studies clearly indicate that transcriptional repressors that downregulate HER2/neu can be effective regimens for cancer treatment in a gene therapy format. More importantly, the tumor-free survival rate of treated animals is dramatically increased under nontoxic doses compared with untreated animals. A phase I clinical trial using E1A-liposome in breast and ovarian patients has recently been completed. Following treatment, we observed downregulation of the HER2/neu protein accompanied by E1A expression in both cancer and noncancer cells. Numbers of tumor cells in the pleural effusion or ascites were found to be dramatically reduced after treatment. Furthermore, apoptosis was strongly induced in the tumor cells. A phase II study has been started to further evaluate therapeutic efficacy and tumor suppression mechanisms of E1A. These studies show the clinical potential of targeting HER2/neu in cancer therapy. Copyright 2001 by W.B. Saunders Company.
UI - 11774200
AU - Lohrisch C; Piccart M
TI - An overview of HER2.
SO - Semin Oncol 2001 Dec;28(6 Suppl 18):3-11
AD - Investigational Drug Branch for Breast Cancer, European Organization for the Research and Treatment of Cancer, Brussels, Belgium.
HER2 is a transmembrane growth factor receptor found in normal and malignant breast epithelial cells. Phosphorylation of the intracellular tyrosine kinase results in intracellular signaling and activation of genes involved in cell growth. Overexpression of HER2 has independent prognostic significance in early breast cancer and may also predict response to hormonal and cytotoxic therapies, although this latter role is less well studied. Prospective stratification of HER2 status in current clinical trials may more accurately delineate these roles. Anti-HER2 therapy, using a humanized monoclonal antibody, has enhanced survival when given with chemotherapy compared with chemotherapy alone in patients with metastatic HER2-overexpressing breast cancer. A potential limitation to its use in the adjuvant setting is the increased incidence of cardiotoxicity in patients treated either concurrently or previously with anthracyclines; carefully designed prospective adjuvant trials are currently being launched. HER2 is a relatively new prognostic marker and holds promise for predicting response to various therapies and for target-specific therapy. Copyright 2001 by W.B. Saunders Company.
UI - 11774205
AU - Hortobagyi GN
TI - Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer.
SO - Semin Oncol 2001 Dec;28(6 Suppl 18):43-7
AD - Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
HER2/neu amplification/overexpression confers more aggressive and malignant characteristics on breast cancer cells. Patients with HER2/neu-amplified breast cancer have a worse prognosis than those with normal HER2/neu expression. Over the past decade, the intracellular signaling pathways associated with this growth factor receptor have been elucidated. Multiple therapeutic strategies that target the HER2/neu oncoprotein are under development. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized monoclonal antibody that binds to the extracellular domain of the HER2/neu receptor, has undergone phase I, II, and III clinical trials. These studies have shown that, as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival. Additional chemotherapy/trastuzumab combinations are under active evaluation, and new schedules of administration are being tested. Thus, trastuzumab is the first successful example of molecularly targeted therapy in the management of metastatic breast cancer. Copyright 2001 by W.B. Saunders Company.
UI - 10885351
AU - Meijers-Heijboer EJ; Verhoog LC; Brekelmans CT; Seynaeve C;
TI - Tilanus-Linthorst MM; Wagner A; Dukel L; Devilee P; van den Ouweland AM; van Geel AN; Klijn JG Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.
SO - Lancet 2000 Jun 10;355(9220):2015-20
AD - Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. METHODS: We assessed presymptomatic DNA testing and prophylactic surgery in 53 consecutive families presenting to the Rotterdam Family Cancer Clinic with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA testing and prophylactic surgery with univariate and multivariate analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275 women and 271 men) or with a 25% risk (136 women) for carrying a mutation were identified and offered a DNA test. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51]; p<0.001). In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pre-test genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a predictor for prophylactic mastectomy but not for prophylactic oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency towards mastectomy at younger ages. INTERPRETATION: In a clinical setting, we show a high demand for BRCA1 and BRCA2 testing by unaffected women at risk, and of prophylactic surgery by unaffected women with the mutation. Young women with children especially opt for DNA testing and prophylactic mastectomy.
UI - 11499060
AU - Frank TS; Critchfield GC
TI - Identifying and managing hereditary risk of breast and ovarian cancer.
SO - Clin Perinatol 2001 Jun;28(2):395-406
AD - Myriad Genetic Laboratories, Salt Lake City, Utah, USA. firstname.lastname@example.org
In the past, all women with a family history of breast or ovarian cancer were considered to be at increased risk of cancer themselves. The discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast and ovarian cancer can be inherited by women as a single-gene autosomal dominant disorder. For such women, evaluation of family history is an important screening tool to identify the possibility of hereditary cancer risk but only genetic testing can provide definitive, individualized risk assessment. Women who have inherited mutations in BRCA1 or BRCA2 now have several medical management options to address their increased risk of cancer. A well-educated community of health care providers and patients can use hereditary risk assessment, including genetic testing, to improve health care.
UI - 11807958
AU - Li JJ; Papa D; Davis MF; Weroha SJ; Aldaz CM; El-Bayoumy K; Ballenger J;
TI - Tawfik O; Li SA Ploidy differences between hormone- and chemical carcinogen-induced rat mammary neoplasms: comparison to invasive human ductal breast cancer.
SO - Mol Carcinog 2002 Jan;33(1):56-65
AD - Hormonal Carcinogenesis Laboratory, Division of Etiology and Prevention of Hormonal Cancers, Kansas Cancer Institute, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
To ascertain differences between solely hormone- and chemical carcinogen-induced murine mammary gland tumors (MGTs), a direct comparison of their ploidy status was assessed. Nuclear image cytometry (NIC) was used to evaluate ploidy in ductal carcinoma in situ (DCIS) and MGTs induced solely by 17beta-estradiol (E(2)) in female A-strain Copenhagen Irish hooded gene rats (ACI) and E(2) plus testosterone propionate in male Noble rats. These results were compared to ploidy data from primary MGTs induced by two synthetic carcinogens, 7,12-dimethylbenz[a]antracene and nitrosomethylurea in female Brown Lewis Norway rats and an environmental carcinogen, 6-nitrochrysene, in female Sprague-Dawley rats. Both DCIS and primary MGTs induced solely by hormones were highly aneuploid (> 84%), whereas MGTs induced by either synthetic or environmental carcinogens were primarily diploid (> 85%). Examination of 76 metaphase plates obtained from eight individual E(2)-induced ACI female rat MGTs revealed the following consistent chromosome alterations: gains in chromosomes 7, 11, 12, 13, 19, and 20 and loss of chromosome 12. On Southern blot analysis, six of nine ACI female rat primary E(2)-induced MGTs (66%) exhibited amplified copy numbers (range: 3.4-6.9 copies) of the c-myc gene. Fluorescence in situ hybridization (FISH) analysis of these MGTs revealed specific fluorescent hybridization signals for c-myc (7q33) on all three homologs of a trisomy in chromosome 7. NIC analysis of 140 successive nonfamilial sporadic invasive human ductal breast cancers (BCs) showed an aneuploid frequency of 61%, while 31 DCISs revealed a 71% aneuploid frequency. These results clearly demonstrate that the female ACI rat E(2)-induced MGTs more closely resemble invasive human DCIS and ductal BC in two pertinent aspects: they are highly aneuploid compared with chemical carcinogen-induced MGTs and exhibit a high frequency of c-myc amplification. Copyright 2002 Wiley-Liss, Inc.
UI - 11781689
AU - Barkardottir RB; Sarantaus L; Arason A; Vehmanen P; Bendahl PO; Kainu T;
TI - Syrjakoski K; Krahe R; Huusko P; Pyrhonen S; Holli K; Kallioniemi OP; Egilsson V; Kere J; Nevanlinna H Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.
SO - Eur J Hum Genet 2001 Oct;9(10):773-9
AD - Department of Pathology, University Hospital of Iceland, Iceland. email@example.com
The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
UI - 11719280
AU - Soulez M; Parker MG
TI - Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling.
SO - J Mol Endocrinol 2001 Dec;27(3):259-74
AD - Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Oligonucleotide microarrays were used to analyse gene expression profiles in human ZR75-1 breast cancer cells in the presence of 17beta-oestradiol and oestrogen antagonists. Differential gene expression of a number of genes was confirmed by quantitative RNA analysis. In addition to known oestrogen-responsive genes, an appreciable number of novel targets were identified, including growth factors and components of the cell cycle, adhesion molecules, enzymes, signalling molecules and transcription factors. The most pronounced oestrogen-sensitive gene was that for the cytochrome P450-IIB enzyme, involved in metabolising steroids and xenobiotics, which was increased 100-fold over a 24 h period. It is a direct target gene for oestrogens, because its expression was increased in the presence of cyclohexamide. In contrast, expression of cytochrome P450-IIB was not detected in human MCF7 breast cancer cells. Expressions of the cationic amino acid transporter E16, gap junction protein and insulin-like growth factor binding protein 4 were also markedly increased by oestrogens, but the kinetics of induction varied according to the target gene. With the exception of the cationic amino acid transporter E16 and the insulin-like growth factor binding protein 4, the expression of the majority of the genes was unaffected by antioestrogen treatment. Further analysis of this set of markers will provide alternative approaches to the investigation of the mitogenicity of oestrogens in breast cancer cells.
UI - 11807777
AU - Buchholz TA; Wu X; Hussain A; Tucker SL; Mills GB; Haffty B; Bergh S;
TI - Story M; Geara FB; Brock WA Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2.
SO - Int J Cancer 2002 Feb 10;97(5):557-61
AD - Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. firstname.lastname@example.org
The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis. Copyright 2001 Wiley-Liss, Inc.
UI - 11733077
AU - Paez G; Richard S; Bianchi MS; Bianchi NO
TI - Loss of heterozygosity (LOH) in 15q26.2-->ter in breast cancer.
SO - Mutat Res 2001 Dec 12;484(1-2):103-6
AD - Multidisciplinary Institute of Cell Biology (IMBICE), C.C. 403, 1900, La Plata, Argentina.
UI - 11754110
AU - Su GH; Song JJ; Repasky EA; Schutte M; Kern SE
TI - Mutation rate of MAP2K4/MKK4 in breast carcinoma.
SO - Hum Mutat 2002 Jan;19(1):81
AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
The stress-activated protein kinase (SAPK) pathways represent phosphorylation cascades that convey pro-apoptotic signals. The relevant inputs include Ras proteins as well as exposure of cells to ultraviolet light, tumor-necrosis factor, and other stress-related inputs. The mitogen-activated protein kinase kinase (MAPKK) homolog MAP2K4 (MKK4, SEK, JNKK1) is a centrally-placed mediator of the SAPK pathways. MAP2K4 mutations or homozygous deletions are reported in about 5% of a wide variety of tumor types. The exception is breast cancer, where genetic inactivation in 3 of 22 (15%) cell lines had suggested that the mutational involvement of MAP2K4 might be accentuated in this tumor type. This finding might have represented an important difference, or solely a chance numerical variation. To address this question, we studied an independent panel of 20 breast cancer cell lines and xenografts for MAP2K4 alterations. We found a splice acceptor mutation accompanied by loss of the other allele in the cell line MPE600. This was the sole alteration in this panel (5% of tumors). These data seem to re-establish a rather consistent rate of genetic inactivation of MAP2K4 among most tumor types, including breast cancer. The genetic evaluation of other mediators of the SAPK pathways might offer insight into a promising, but as yet poorly defined, tumor-suppressive system. Copyright 2001 Wiley-Liss, Inc.
UI - 11754111
AU - Armakolas A; Ladopoulou A; Konstantopoulou I; Pararas B; Gomatos IP;
TI - Kataki A; Konstadoulakis MM; Stathopoulos GP; Markopoulos C; Leandros E; Gogas I; Yannoukakos D; Androulakis G BRCA2 gene mutations in Greek patients with familial breast cancer.
SO - Hum Mutat 2002 Jan;19(1):81-2
AD - Laboratory of Surgical Research, A' Propaedeutic Surgical Clinic, Athens Medical School, Hippokrateion Hospital, Athens, Greece.
Family history is a well-recognized risk factor for the development of breast cancer. The isolation of BRCA1 and BRCA2 genes, the two major predisposing genes in familial and to early onset breast and ovarian cancer, has resulted to the identification of a large number of families with mutations in these two genes. Despite the large number of distinct mutations detected in both genes, several mutations have been found to recur in unrelated families of diverse geographical origin. We have analyzed 27 Greek patients with familial breast cancer the majority of those having one first and one second degree relatives affected and 28 patients with sporadic breast cancer for BRCA2 germline mutations. The techniques used were single-strand conformation polymorphism analysis (SSCP) followed by sequencing. Furthermore, the clinical presentation and prognosis of BRCA2 associated breast cancer cases was compared to 20 adequately matched for age and date of diagnosis (within one year) sporadic breast cancer patients. We identified three novel BRCA2 mutations (3058delA, 6024delTA, and 4147delG) in the ovarian cancer cluster region (OCCR) and one already known (2024del5) germline BRCA2 gene mutation in five different breast cancer families. The 4147delG mutation was detected in two unrelated patients. BRCA2 germline mutations were correlated with early-onset breast cancer RR=4.77 (95% CI: 0.666-34.463). Although patients with BRCA2 germline mutations did not have a distinct histological phenotype they had an improved overall survival (100% vs 65%). Our findings suggest that there is a cluster of novel mutations in exons 10 and 11 in Greek patients with familial breast cancer. These mutations appear to have a milder clinical phenotype when compared to the rest of the study group. Copyright 2001 Wiley-Liss, Inc.
UI - 11782367
AU - Jeffy BD; Chirnomas RB; Chen EJ; Gudas JM; Romagnolo DF
TI - Activation of the aromatic hydrocarbon receptor pathway is not sufficient for transcriptional repression of BRCA-1: requirements for metabolism of benzo[a]pyrene to 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.
SO - Cancer Res 2002 Jan 1;62(1):113-21
AD - Cancer Biology Interdisciplinary Program, Department of Nutritional Sciences, The University of Arizona, Tucson, Arizona 85721, USA.
Reduction of BRCA-1 expression through nonmutational events may be a predisposing event in the onset of sporadic breast cancer. In this study, we investigated the mechanisms through which the environmental carcinogen benzo[a]pyrene (B[a]P) lowered BRCA-1 mRNA levels in breast cancer MCF-7 cells. We report that B[a]P does not compromise the stability of BRCA-1 mRNA, but represses transcriptional activity of a 1.69-kb BRCA-1 (pGL3-BRCA-1) promoter fragment that contains both exon-1A and exon-1B transcription start sites. The loss of BRCA-1 promoter activity was accompanied by accumulation of CYP1A1 and BAX-alpha mRNA and p53 and p21 protein, whereas levels of Bcl-2 mRNA were reduced. The aromatic hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is not metabolized, did not affect BRCA-1 promoter activity or the cellular levels of BRCA-1 and p53 protein, but it did induce a CYP1A1-like promoter. Conversely, treatment with the B[a]P metabolite 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) repressed BRCA-1 promoter activity and protein, while increasing p53 and p21 protein levels. Transient expression of dominant-negative p53 ((175)Arg-->His) counteracted the detrimental effects of BPDE on BRCA-1 promoter activity and protein levels. Similarly, treatment with B[a]P, TCDD, or BPDE failed to repress transcription from the pGL3-BRCA-1 construct transfected into ZR75.1 breast cancer cells containing mutated p53 ((152)Pro-->Leu). We conclude that activation of the aromatic hydrocarbon receptor is not sufficient for down-regulation of BRCA-1 transcription, which is, however, inhibited by the B[a]P metabolite BPDE through a p53-dependent pathway.
UI - 11782349
AU - Zou Y; Peng H; Zhou B; Wen Y; Wang SC; Tsai EM; Hung MC
TI - Systemic tumor suppression by the proapoptotic gene bik.
SO - Cancer Res 2002 Jan 1;62(1):8-12
AD - Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Metastatic breast cancer requires systemic treatment. We have developed a systemic gene therapy approach for breast cancer, consisting of a nonviral gene delivery system (SN) and a proapoptotic gene, bik. The transfection efficiency of SN carrying a reporter gene was 5-10 times higher than the common nonviral agents Fugene-6 and Lipofectamine in the presence of serum. The SN-bik gene complex induced significant apoptosis in four breast cancer cell lines in vitro as well as in orthotopic tumor tissues in nude mice. Systemically administrated SN-bik significantly inhibited the growth and metastasis of human breast cancer cells implanted in nude mice and prolonged the life span of the treated animals. This study demonstrates that SN-bik is a promising approach for further development as a potential therapeutic agent of cancer.
UI - 11802208
AU - de la Hoya M; Osorio A; Godino J; Sulleiro S; Tosar A; Perez-Segura P;
TI - Fernandez C; Rodriguez R; Diaz-Rubio E; Benitez J; Devilee P; Caldes T Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing.
SO - Int J Cancer 2002 Feb 1;97(4):466-71
AD - Laboratory of Molecular Oncology, Hospital Universitario San Carlos, Madrid, Spain.
Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2- from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics. Copyright 2001 Wiley-Liss, Inc.
UI - 11802209
AU - Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer
TI - Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
SO - Int J Cancer 2002 Feb 1;97(4):472-80
AD - Department of Medical Genetics, Ludwig-Maximilians University, Munich, Germany. email@example.com
The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than (1/3) of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure. Copyright 2001 Wiley-Liss, Inc.
UI - 11790987
AU - Polyak K
TI - Molecular alterations in ductal carcinoma in situ of the breast.
SO - Curr Opin Oncol 2002 Jan;14(1):92-6
AD - Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. Kornelia_Polyak@dfci.harvard.edu
Despite recent improvements in the breast cancer mortality rate, breast cancer remains the most common cancer and the second leading cause of cancer-related deaths in US women. A decreasing trend in mortality rates is caused by advances in early detection and, to a lesser degree, in cancer therapies. With the increased utilization of mammography, one of the earliest detectable breast tumors, ductal carcinoma in situ, has become the most rapidly increasing subset of breast cancers. Contrary to the dramatic improvement in our ability to detect ductal carcinoma in situ, the pathophysiology of this disease is still poorly understood. Many molecular studies have been performed in ductal carcinoma in situ lesions with the aims of identifying genes involved in breast cancer initiation and progression, defining the relation between in situ and invasive carcinomas, and identifying clinically useful markers for breast cancer diagnosis, prognostication, prevention, and treatment.
UI - 11826460
AU - Levin T; Reichelt J; Heimdal K; Moller P
TI - [Information to families with hereditary breast and ovarian cancer]
SO - Tidsskr Nor Laegeforen 2001 Nov 20;121(28):3292-4
AD - Seksjon for genetisk veiledning Avdeling for kreftgenetikk Det Norske Radiumhospital 0310 Oslo. firstname.lastname@example.org
BACKGROUND: Under Norwegian legislation, persons at risk should make the initial contact with the proper health personnel, and not vice versa. It may be argued that the physician should be allowed to make contact with persons at risk of preventable or curable disorders. MATERIAL AND METHODS: We identified all first-degree relatives of all 75 BRCA1 mutation carriers diagnosed within a given period of time and asked them whether or not they had been informed by their relatives. RESULTS: After two years, 60/63 (95%) adult sisters and daughters had made contact with us; the remaining three (5%) had been informed. In comparison, 18/45 (40%) adult brothers and sons had contacted us. INTERPRETATION: The legislation constituted no barrier to offering health services to the target group. Information on our services had reached all close relatives who could benefit from them. This may be representative for curable inherited disorders. We examined inherited cancer limited to females; similar studies on inherited cancers in males and on other curable inherited disorders should be performed. Outside the framework of the present study, we are aware of rare examples of distant cousins who have not been properly informed through their families. One legally acceptable way of identifying mutation carrier families is to test all patients with breast or ovarian cancer for causative mutations. Health services should be monitored to make future decisions based on empirical evidence.
UI - 11590619
AU - Andersen CL; Hostetter G; Grigoryan A; Sauter G; Kallioniemi A
TI - Improved procedure for fluorescence in situ hybridization on tissue microarrays.
SO - Cytometry 2001 Oct 1;45(2):83-6
AD - Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4465, USA.
BACKGROUND: The recently developed tissue microarray (TMA) technology allows the arrangement of up to a thousand tissue specimens on a single microscope slide. This technology enables researchers to perform gene copy number studies on very large series of archival formalin-fixed tissues using fluorescence in situ hybridization (FISH). However, the hybridization properties of individual archival specimens can vary considerably. Therefore a highly optimized protocol is needed to fulfill the task of producing evaluable hybridization signals simultaneously in hundreds of specimens in a TMA. METHODS: The performance of two different FISH protocols, the standard protocol for paraffin embedded tissues and our new optimized protocol, was tested on TMAs using probes for the HER-2 and ZNF217 genes as well as the chromosome 17 centromere. RESULTS: The new protocol resulted in greatly increased signal intensity and an almost 30% increase in the number of tissue samples with evaluable hybridization signals. CONCLUSIONS: Our improved protocol for FISH on TMAs provides standardized hybridization conditions leading to high-quality hybridization signals in the majority of specimens. The increases in the signal intensity and the number of evaluable samples are extremely important for the successful analyses of TMAs by FISH and will allow the utilization of the TMA technology in its full potential.
UI - 11785296
AU - Mandel'shtam MIu; Golubkov VI; Lamber EP; Shapiro IM; Brezhneva TV;
TI - Semiglazov VF; Lipovetskii BM; Hanson KP; Gaitskhoki VS [Search for frequently encountered mutations in genes predisposing to breast cancer]
SO - Genetika 2001 Dec;37(12):1681-6
AD - Research Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg, 197376 Russia.
DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in