National Cancer Institute®
Last Modified: November 21, 2001
UI - 21274388
AU - Nagasawa H; Kusakawa S
TI - Two inbred strains of mice with high and low mammary tumor potentials established from the same basal stock of Swiss albino (SHN and SLN): history of mammary tumorigenesis and reproduction after the 30th generation of full-sib mating.
SO - Exp Anim 2001 Apr;50(2):167-71
AD - Experimental Animal Research Laboratory, Meiji University, Tama-ku, Kawasaki 214-8571, Japan.
We established SHN and SLN strains of mice with a high and a low mammary tumor potentials from the same basal stock of Swiss albino. The selection history of females (mothers) for subsequent generations, mammary tumorigenesis and reproduction up to recent generations are presented and compared with the results up to F30 published in 1979. The changes with generation of each parameter varied in both strains except the conditions of female (mother) selection for subsequent generations, which were generally constant. However, the fluctuations in parameters up to F30 became generally smaller with advancing generations. Based on the fluctuations from generation to generation of mammary tumorigenic and reproductive parameters, an interdependency between mammary tumor potential and reproductivity is suggested in SLN, but less so in SHN. The pup growth rate was increased and associated with selection for mammary tumorigenesis in SHN; this parameter is usually used as an indicator of mother lactational performance in mice. The significance of selection for mammary tumor potential in association with reproductivity was further discussed.
UI - 21283527
AU - Liehr JG
TI - Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development.
SO - Hum Reprod Update 2001 May-Jun;7(3):273-81
AD - Stehlin Foundation for Cancer Research at Christus St Joseph Hospital, Houston, Texas 77003, USA. firstname.lastname@example.org
Oestrogens, including the natural hormones oestrone and oestradiol, induce various tumours in laboratory animals and have been recognized to be carcinogens in humans, raising the risk for breast and uterine cancer. As part of the search for the mechanism of hormone-induced carcinogenesis, various types of DNA damage have been detected which have been induced by oestrogens in cell-free systems, in cells in culture, or in vivo. Nevertheless, oestrogens have been postulated to act only as promoters of mammary carcinogenesis by receptor-mediated growth stimulation without consideration of their genotoxicity because these hormones failed to induce mutations in commonly used assays. More recently, oestradiol-induced numerical chromosomal changes (aneuploidy) and structural chromosomal aberrations have been detected in cells in culture and in hamster kidney, a target of oestrogen-induced cancer. In this animal model, oestradiol generates c-myc gene amplification and microsatellite instability. Mutations of the hprt gene have been induced by oestradiol in V79 cells and by catecholoestrogen metabolites in Syrian hamster embryo cells. Sequencing of this gene isolated from V79 mutant clones revealed point mutations and deletions. It is concluded that oestradiol plays a dual role as mutagen/carcinogen and as growth-stimulating hormone in the induction of tumours.
UI - 21347324
AU - Chappuis PO; Hamel N; Paradis AJ; Deschenes J; Robidoux A; Potvin C;
TI - Cantin J; Tonin P; Ghadirian P; Foulkes WD Prevalence of founder BRCA1 and BRCA2 mutations in unselected French Canadian women with breast cancer.
SO - Clin Genet 2001 Jun;59(6):418-23
AD - McGill University Health Centre Research Institute, McGill University, Montreal, Quebec, Canada.
The frequency of BRCA1 and BRCA2 mutations in women with breast cancer varies according to the age at diagnosis, family history of cancer, and ethnicity/country of origin. We set out to estimate the frequency of seven previously described founder mutations in BRCA1 and BRCA2 in all eligible French Canadian women diagnosed with invasive breast cancer at one Montreal hospital over a 20-month period. One hundred and ninety-two patients were eligible and 127 (66.2%) provided blood for genetic testing. We identified 4 women who carried a founder mutation (3.1%, 95% confidence interval 0.9-7.9%) in this population. Interestingly, all the mutations were in BRCA2. The mean age at diagnosis for mutation carriers was 51.2 years (range 49.1-53.5). Two of these 4 cases were lobular invasive carcinomas and 2 were ductal carcinomas, histological grade 1 or 2. Despite a small tumor size (< or =20 mm), axillary nodal involvement was present in 3 women. Estrogen receptors were strongly expressed in all cases. Two of the 4 cases reported a strong family history of breast cancer, but a family history of site-specific breast cancer was a relatively poor indicator of the presence of BRCA2 mutations. The absence of BRCA1 mutations may be a result of chance, but may also reflect different geographical origins of the most common BRCA1 mutations within the French Canadian population.
UI - 21367957
AU - Matsumoto Y; Takano H; Kunishio K; Nagao S; Fojo T
TI - Expression of drug resistance genes in VP-16 and mAMSA-selected human carcinoma cells.
SO - Jpn J Cancer Res 2001 Jul;92(7):778-84
AD - Department of Neurological Surgery, Kagawa Medical University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. email@example.com
The cell lines described in the present study were isolated as part of an effort to understand resistance to topoisomerase (topo) II inhibitors. To that end, 50 sublines were isolated from four human breast cancer cell lines, i.e., MCF-7, T47D, MDA-MB-231, and ZR-75B. As an initial step, a concentration that would be lethal to the majority of cells (IC99) was selected for both VP-16 and mAMSA, for each cell line. The identification of an increasing number of putative drug resistance-related proteins provided the opportunity to examine expression of the corresponding genes in the selected cell lines. Northern blot analysis revealed different responses to the selecting agents in the different cell lines. Previous studies examining expression of multidrug resistance (MDR)-1 in resistant cell lines had found undetectable levels in all cells. In the ZR-75B sublines, increased expression of MDR-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) was observed, and when the relative levels of overexpression were compared, a high correlation was found. In contrast, increased expression of MRP was observed in some of the MDA-MB-231 sublines, without a concomitant increase in cMOAT expression. Finally, in both T47D and MCF-7 sublines, increased expression of cMOAT or MRP was observed infrequently, and where it occurred, was of a much smaller magnitude. In the analysis of expression of MRP, the highest levels were found in the ZR-75B and MDA-MB-231 sublines, with lower levels in the MCF-7 and T47D clones. Similarly, differences in the expression of topo IIalpha were observed among the sublines. Although the differences in expression appear to depend on the parental cell line from which the resistant sublines were derived, a strong correlation was observed between the expression of MRP and the levels of topo IIalpha. Cell lines with low levels of MRP had lower levels of topo IIalpha, while those with high levels of MRP maintained higher levels of topo IIalpha. While a reduced topo IIalpha level was common, there did not appear to be a compensating increase in the expression of topo IIbeta or topo I or casein kinase (CK) IIalpha in any of the cell lines. While the possibility that such compensation could occur has been discussed and even reported in some cell lines, such an adaptation was not observed in the present study, suggesting that it is not common.
UI - 21385662
AU - Teixeira MR; Tsarouha H; Kraggerud SM; Pandis N; Dimitriadis E; Andersen
TI - JA; Lothe RA; Heim S Evaluation of breast cancer polyclonality by combined chromosome banding and comparative genomic hybridization analysis.
SO - Neoplasia 2001 May-Jun;3(3):204-14
AD - Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. firstname.lastname@example.org
Cytogenetically unrelated clones have been detected by chromosome banding analysis in many breast carcinomas. Because these karyotypic studies were performed on short-term cultured samples, it may be argued that in vitro selection occurred or that small clones may have arisen during culturing. To address this issue, we analyzed 37 breast carcinomas by G-banding and comparative genomic hybridization (CGH), a fluorescent in situ hybridization--based screening technique that does not require culturing or tumor metaphases. All but two of the 37 karyotypically abnormal cases presented copy number changes by CGH. The picture of genomic alterations revealed by the two techniques overlapped only partly. Sometimes the CGH analysis revealed genomic imbalances that belonged to cell populations not picked up by the cytogenetic analysis and in other cases, especially when the karyotypes had many markers and chromosomes with additional material of unknown origin, CGH gave a more reliable overall picture of the copy number gains and losses. However, besides sometimes revealing cell populations with balanced chromosome aberrations or unbalanced changes that nevertheless remained undetected by CGH, G-banding analysis was essential to understand how the genomic imbalances arose in the many cases in which both techniques detected the same clonal abnormalities. Furthermore, because CGH pictures only imbalances present in a significant proportion of the test sample, the very detection by this technique of imbalances belonging to apparently small, cytogenetically unrelated clones of cells proves that these clones must have been present in vivo. This constitutes compelling evidence that the cytogenetic polyclonality observed after short-term culturing of breast carcinomas is not an artifact.
UI - 21396680
AU - Foster JS; Henley DC; Ahamed S; Wimalasena J
TI - Estrogens and cell-cycle regulation in breast cancer.
SO - Trends Endocrinol Metab 2001 Sep;12(7):320-7
AD - Dept of OB/GYN, Graduate School of Medicine, University of Tennessee, Knoxville, TN 37920, USA.
Clinical and experimental data have established that the leading cause of sporadic female breast cancer is exposure to estrogens, predominantly 17beta-estradiol. Recent advances in the understanding of cell-cycle control mechanisms have been applied to outline the molecular mechanisms through which estrogens regulate the cell cycle in cultured breast cancer cells, in particular, in MCF-7 cells. Here, we discuss how estrogens exert control over several key G1 phase cell-cycle regulators, namely cyclin D1, Myc, Cdk2, Cdk4, Cdk inhibitors and Cdc25A. Although the molecular mechanisms underlying estrogenic regulation of G1 phase regulators are far from clear, current evidence indicates that estrogens might regulate several key molecules required for S phase entry, this regulation being independent of cell-cycle transit per se.
UI - 21436642
AU - Coulson AS; Glasspool DW; Fox J; Emery J
TI - RAGs: A novel approach to computerized genetic risk assessment and decision support from pedigrees.
SO - Methods Inf Med 2001;40(4):315-22
AD - Advanced Computation Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
OBJECTIVES: To assist general practitioners in evaluating patients' genetic risk of cancer on the basis of family history data. METHODS: A new computer application, RAGs (Risk Assessment in Genetics), has been developed to help doctors create graphical family trees and assess the genetic risk of breast and colorectal cancer. RAGs possesses two features that distinguish it from similar software: (i) a user-centred design, which takes into account the requirements of the doctor-patient encounter; (ii) effective and accessible risk reporting by employing qualitative evidence for or against increased risk, which is more easily understood than numerical probabilities. The system allows any rule-based genetic risk guideline to be implemented, and may be readily modified to cater for the varying degrees of information required by different specialists. RESULTS: RAGs permits fast, accurate data entry, and results in more appropriate management decisions than those made via other techniques. In addition, RAGs enables both the clinician and the patient to understand how it arrives at its conclusions, since the use of qualitative evidence allows the program to provide explanations for its reasoning. CONCLUSIONS: The RAGs system promises to help practitioners be more effective gatekeepers to genetic services. It may empower doctors both to make an informed choice when deciding to refer patients who are at increased genetic risk of breast or colorectal cancer, and to reassure those who are at low risk.
UI - 21446332
AU - Green MJ; Biesecker BB; McInerney AM; Mauger D; Fost N
TI - An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility.
SO - Am J Med Genet 2001 Sep 15;103(1):16-23
AD - Department of Humanities, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA. email@example.com
As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P <.0001). Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group (P =.048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P =.0002; odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing. Copyright 2001 Wiley-Liss, Inc.
UI - 21446333
AU - Green MJ; McInerney AM; Biesecker BB; Fost N
TI - Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor.
SO - Am J Med Genet 2001 Sep 15;103(1):24-31
AD - Department of Humanities, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA. firstname.lastname@example.org
The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling.
UI - 21439123
AU - Ghadersohi A; Sood AK
TI - Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen.
SO - Clin Cancer Res 2001 Sep;7(9):2731-8
AD - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
PURPOSE: There is a need to identify novel breast tumor-associated molecules with a potential as diagnostic/prognostic markers of breast cancer as well as targets of vaccine and drug discovery against this cancer. EXPERIMENTAL DESIGN: We used a combination of digital differential display and reverse transcription-PCR (RT-PCR) methods to identify breast tumor-associated cDNAs. RESULTS: It was found that prostate epithelium-derived Ets transcription factor (PDEF) and five other cDNAs occur at high frequency in the cDNA libraries from normal human breast tissue and human breast tumors. In contrast, these cDNAs are either undetectable or present at low frequencies in the cDNA libraries from other normal human tissues. RT-PCR expression analysis of PDEF showed it to be overexpressed in 14 of 20 primary human breast tumors and in one metastases tested. Also, consistent with the digital differential display data, RT-PCR analysis of PDEF expression showed highly restricted expression in normal human tissues. Furthermore, we show that PDEF transcript levels are 192-fold higher in the peripheral blood of a breast cancer patient in comparison with two normal individuals and another breast cancer patient. In contrast to PDEF, RT-PCR analysis of the expression of the other three cDNAs, including MYL5, Hs.44017, and Hs.215937, showed that these cDNAs are expressed in several normal human tissues. CONCLUSIONS: These results suggest that PDEF is a breast tumor-associated cDNA and should be further evaluated for its potential as a breast tumor marker and a breast tumor antigen.
UI - 21439135
AU - Kataoka A; Sadanaga N; Mimori K; Ueo H; Barnard GF; Sugimachi K; Auclair
TI - D; Chen LB; Mori M Overexpression of HRad17 mRNA in human breast cancer: correlation with lymph node metastasis.
SO - Clin Cancer Res 2001 Sep;7(9):2815-20
AD - Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan.
PURPOSE: A novel human gene, designated HRad17, was identified as the human homologue of the Rad17 of Schizosaccharomyces pombe and Rad24 of Saccharomyces cerevisiae. In yeast, these genes play a critical role in maintaining genomic stability. The aim of this study was to evaluate the expression of HRad17 in human breast cancer. EXPERIMENTAL DESIGN: We investigated HRad17 mRNA expression in 64 cases of human breast cancer by means of reverse-transcription-PCR, in situ hybridization, and immunohistochemistry. RESULTS: The HRad17 mRNA was overexpressed in 35 cases (54.7%). Twenty-four (68.6%) of 35 cases with HRad17 overexpression in cancer tissues were node-positive, whereas only 8 (27.6%) of 29 cases without HRad17 overexpressions were node-positive. The expression of HRad17 mRNA correlated with both lymph node metastasis (P = 0.001) and high Ki67 labeling index (P = 0.006). Although not significantly different, expression of HRad17 mRNA tended to correlate with tumor size (P = 0.06) and expression of mutant p53 protein (P = 0.10). Furthermore, expression of HRad17 mRNA was an independent predictor of axillary lymph node metastasis as well as of lymphatic permeation by multivariate analysis (P < 0.0001). CONCLUSIONS: Our study demonstrates that HRad17 might be related to the development of lymph node metastasis in human breast cancers. Although its function still remains unclear, the expression of HRad17 mRNA could open up a new window for the diagnostic staging and treatment of human breast cancers.
UI - 21450459
AU - Lahti-Domenici J; Rapakko K; Paakkonen K; Allinen M; Nevanlinna H;
TI - Kujala M; Huusko P; Winqvist R Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):120-3
AD - Department of Clinical Genetics, University of Oulu/Oulu University Hospital, P.O. Box 22, FIN-90220, Oulu, Finland.
In the Finnish population, identified mutations in BRCA1 and BRCA2 account for a less than expected proportion of hereditary breast and ovarian cancer. All previous studies performed in our country have concentrated on finding germ-line mutations in the coding and splice-site regions of these two genes. Therefore, we wanted to use a different methodological approach and search for large genomic rearrangements, to exclude the possibility of biased BRCA1 and BRCA2 mutation spectra due to known limitations of the previously used PCR-based detection methods. Our results support earlier notions that other genes than BRCA1 and BRCA2 will explain a majority of the still unexplained cases of hereditary susceptibility to breast and ovarian cancer.
UI - 21450463
AU - Hoff C; Mollenhauer J; Waldau B; Hamann U; Poustka A
TI - Allelic imbalance and fine mapping of the 17p13.3 subregion in sporadic breast carcinomas.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):145-9
AD - Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Chromosome arm 17p is frequently altered in a variety of human cancers, especially in breast cancer, and allelic imbalances (AIs) in the region 17p13.1 do not always coincide with mutations in the TP53 gene. A second interval that frequently shows AIs at 17p is the chromosomal band 17p13.3. This region is suspected to harbor another tumor suppressor gene. In order to get more information concerning the pattern of AIs in 17p13.3, we performed analysis of AI of 49 breast carcinomas at 6 polymorphic loci in 17p13.3. Eighty-six percent of the tumors present AI at least at one marker in 17p13.3. Among all loci tested, the highest percentage of Al was observed at loci D17S5 (77%) and D17S1528 (72%). According to these results, a minimal region of deletion could be determined between the markers D17S28 and D17S5. Fine mapping of this region revealed that the size of the deleted region is about 100-150 kb. Furthermore, a subset of the patients shows two other areas with AI close to the markers D17S1574/D17S513 and D17S849, respectively.
UI - 21468601
AU - Gershoni-Baruch R; Dagan E; Israeli D; Kasinetz L; Kadouri E; Friedman E
TI - Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women.
SO - Eur J Cancer 2000 Dec;36(18):2313-6
AD - Institute of Human Genetics, Rambam Medical Center, Haifa, Israel. email@example.com
The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, hyperhomocysteinaemia and increased risk for atherosclerosis in homozygotes. We examined the frequency of this mutation and its association with disease pattern in 491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n = 136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2 mutation carriers, genotyped for the three predominant Jewish founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes were equally distributed among women with sporadic breast and/or ovarian cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205; 21.0%) (P=non-significant). 677T homozygotes were equally distributed among women diagnosed with breast cancer prior to (22/122; 18.0%) and after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes in manifesting cancer (32/136; 23.5%) and asymptomatic individuals (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among women with bilateral breast cancer and those with both breast and ovarian carcinoma than among those with unilateral breast cancer (64/365; 17.5%). Differences in morbidity (one versus multiple breast/ovarian tumours) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations. Confirmation of these data, namely, that the 677T allele is significantly more common in cases of bilateral breast cancer or combined breast and ovarian cancer would have important clinical implications.
UI - 21468609
AU - Miyoshi Y; Iwao K; Ikeda N; Egawa C; Noguchi S
TI - Genetic polymorphism in CYP17 and breast cancer risk in Japanese women.
SO - Eur J Cancer 2000 Dec;36(18):2375-9
AD - Department of Surgical Oncology, Osaka University Medical School, Suita-shi, Japan.
A case-control study was conducted to investigate the association of two genetic polymorphisms (1931T/C and 1951G/A) in the promoter region of the CYP17 gene with breast cancer risk in Japanese women. No significant association was observed between CYP17 polymorphism(1951G/A) and breast cancer risk (odds ratio (OR) = 1.71, 95% confidence interval (CI): 0.28-1.84). In contrast, a significant increase in breast cancer risk (OR= 1.82. 95% CI: 1.07-3.12) was observed in CYP17(1931C/C) homozygotes compared with CYP17(1931T/C) heterozygotes and CYP17(1931T/T) homozygotes when women aged > or = 55 years were considered, but such a significant increase was not observed when women aged < or = 54 years were considered (OR = 0.96, 95% CI: 0.56-1.63). These results suggest that CYP17 polymorphism(1931T/C) would be useful in the selection of Japanese women at a high risk for developing breast cancer at the age of > or = 55 years.
UI - 21218915
AU - Jacquemier J; Lidereau R; Birnbaum D; Eisinger F; Sobol H
TI - Assessing the risk of BRCA1-associated breast cancer using individual morphological criteria.
SO - Histopathology 2001 Apr;38(4):378-9
UI - 21262969
AU - Roy SK; Trividi AH; Bakshi SR; Patel SJ; Shukla PS; Shah AD; Majithiya
TI - DB; Patel DD; Shah PM A study of chromosome aneuploidy in hereditary breast cancer patients and their healthy blood relatives.
SO - J Exp Clin Cancer Res 2001 Mar;20(1):103-9
AD - Dept. of Surgical Oncology, The Gujarat Cancer Society, Asarwa, Ahmedabad, India. firstname.lastname@example.org
Chromosomal abnormalities that may predispose a group of individuals to develop certain neoplasms have been reported in lymphocytes. We evaluated cytogenetic abnormalities in 21 histopathologically confirmed primary breast cancer patients (BCPs), 52 healthy blood relatives (HBRs), belonging to 19 hereditary breast cancer families (HBFs) and 25 females as control. Phytohemagglutinin stimulated peripheral blood lymphocyte (PBL) cultures were used to study the chromosomal abnormalities in BCPs and their HBRs. Short term culture of the tumor tissue was also carried out in defined growth medium. Suitable metaphases (11 to 55) from tumors and a minimum of 100 metaphases from PBL were karyotyped for the cytogenetic analysis. Heterogeneous population of cells with random and nonrandom chromosomal abnormalities was noticed in tumors. In control groups 2-5% of metaphases showed numerical abnormalities, whereas this phenomenon was observed in 3-18% of metaphases in HBRs and 3-23% of metaphases in BCPs. In tumor tissue, 47.05% of BCPs showed numerical abnormalities in more than 16 metaphases. In lymphocytes, this event was observed in 33.33% of BCPs and 13.14% of HBRs. In controls 1.28%, in BCPs 52.04% (tumor) and 13.42% (lymphocytes), and in HBRs 9.03% of metaphases were found aneuploid. Statistically it was highly significant (Fisher's exact test, P<0.00001). In lymphocytes of BCPs, chromosomes 1, 6, 8, 9, 15, 17, 18, 20, and X and in HBRs, chromosomes 8, 15, 17, 18, and X were frequently involved. It can be inferred from the findings that the above mentioned chromosomes may have an important role in early stage of breast carcinogenesis in BCFs. Moreover, presence of similar abnormalities in HBR indicates inherited pattern of this genetic error among them.
UI - 21283055
AU - Bergthorsson JT; Ejlertsen B; Olsen JH; Borg A; Nielsen KV; Barkardottir
TI - RB; Klausen S; Mouridsen HT; Winther K; Fenger K; Niebuhr A; Harboe TL; Niebuhr E BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age.
SO - J Med Genet 2001 Jun;38(6):361-8
AD - Department of Medical Genetics, Institute for Medical Biochemistry and Genetics, Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark. email@example.com
INTRODUCTION: A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. OBJECTIVES: To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. SUBJECTS: From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. METHODS: DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry. RESULTS: Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. CONCLUSIONS: A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly when combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.
UI - 21317608
AU - Gad S; Scheuner MT; Pages-Berhouet S; Caux-Moncoutier V; Bensimon A;
TI - Aurias A; Pinto M; Stoppa-Lyonnet D Identification of a large rearrangement of the BRCA1 gene using colour bar code on combed DNA in an American breast/ovarian cancer family previously studied by direct sequencing.
SO - J Med Genet 2001 Jun;38(6):388-92
UI - 21468783
AU - Magnet KJ; Orr MS; Cleveland JL; Rodriguez-Galindo C; Yang H; Yang C; Di
TI - YM; Jain PT; Gewirtz DA Suppression of c-myc expression and c-Myc function in response to sustained DNA damage in MCF-7 breast tumor cells.
SO - Biochem Pharmacol 2001 Sep 1;62(5):593-602
AD - Department of Medicine, Medical College of Virginia at Virginia Commonwealth University, Richmond 23298-0230, USA.
The topoisomerase II inhibitors teniposide (VM-26), doxorubicin, and amsacrine (m-AMSA), as well as ionizing radiation, induce a transient suppression of c-myc mRNA, which correlates with growth inhibition of MCF-7 breast tumor cells. To further assess the involvement of c-mvc in the DNA damage-induced signal transduction pathways of the breast tumor cell, we determined the influence of sustained DNA damage on c-myc expression, c-Myc protein levels and c-Myc function. Continuous exposure of MCF-7 breast tumor cells to VM-26 induced DNA strand breaks that were sustained for at least 9 hr. DNA strand breakage was accompanied by a decline in c-myc transcripts and c-Myc protein levels by >90% after VM-26 exposure for 24 hr. The activity of a transcriptional target of the c-Myc protein, ornithine decarboxylase, was reduced by approximately 75% within 9 hr of DNA damage, in parallel to the declines in c-myc mRNA and protein levels. Extended exposure to VM-26 resulted in an initial loss of approximately 35% of the cell population followed by the death of additional cells such that by 72 hr only 50% of the cells were viable. Although apoptosis was evident 72 hr after initiating drug exposure [based on cell cycle analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and an assessment of cell morphology], the primary phase of cell killing, which occurred during the first 24 hr was non-apoptotic. These studies indicate that non-apoptotic pathways can also mediate cell death in the breast tumor cell and support the role of c-myc expression, c-Myc protein, and c-Myc function as elements of the DNA damage response pathway in the breast tumor cell.
UI - 99296429
AU - Shevde LA; Joshi NN; Advani SH; Nadkarni JJ
TI - Impaired T lymphocyte function and differential cytokine response pattern in members from cancer families.
SO - Nat Immun 1998;16(4):146-56
AD - Immunology Division, Cancer Research Institute, Parel, Mumbai, India.
In an attempt to understand the basis of lowered natural killer (NK) and T cell functions in unaffected members from cancer families, we investigated cytotoxic T lymphocyte function (CD3-directed lysis) and the ability of the lymphocytes to respond to cytokines such as IL-2, IFN-alpha and IL-12. We observed lower CD3-mediated cytotoxic activity in these individuals supported by significantly lower numbers of circulating CD3+ lymphocytes. The cytokine treatment studies revealed impaired response to IFN-alpha and IL-12 in unaffected members and breast cancer patients. The observations presented herein not only reinforce our earlier finding that lower NK and T lymphocyte function may be a feature of cancer families, but also suggest that such impaired responses may be one of the factors contributing to lower cytotoxic potential of the circulating lymphocytes.
UI - 21443275
AU - Otte M; Zafrakas M; Riethdorf L; Pichlmeier U; Loning T; Janicke F;
TI - Pantel K MAGE-A gene expression pattern in primary breast cancer.
SO - Cancer Res 2001 Sep 15;61(18):6682-7
AD - Molekulare Onkologie, Frauenklinik, Universitatsklinikum Hamburg-Eppendorf, Germany.
Melanoma antigen (MAGE)-A-derived peptides elicit a strong in vitro T-cell response against tumor cells. For determination of MAGE-A1, -2, -3, -4, -6, and -12 expression profile in invasive breast cancer, we developed a multiplex seminested reverse transcription-PCR-method. In total, 18 of 67 (27%) tumors were positive for at least one of these MAGE transcripts, and the expression pattern was heterogeneous: MAGE-A1 was positive in 4 of 67 (6%), MAGE-A2 in 13 of 67 (19%), MAGE-A3 in 7 of 67 (10%), MAGE-A4 in 9 of 67 (13%), MAGE-A6 in 10 of 67 (15%), and MAGE-A12 in 6 of 67 (9%) patients. The MAGE-A transcripts were more frequently expressed in ductal breast carcinomas compared with other histomorphological types. We observed a preferential expression of MAGE-A in patients at a higher risk of recurrence: those harboring tumors with high levels of the protease urokinase-type plasminogen activator and its inhibitor plasminogen activator inhibitor 1, high score of the Ki-67 proliferation antigen, and lesser degree of differentiation. Our findings suggests a potential involvement of MAGE-A in tumor progression, with potential implications for active immunotherapy.
UI - 21443287
AU - Lu D; Kiriyama Y; Lee KY; Giguere V
TI - Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors.
SO - Cancer Res 2001 Sep 15;61(18):6755-61
AD - Molecular Oncology Group, McGill University Health Centre, Montreal, Quebec, H3A 1A1 Canada.
The estrogen-receptor-related receptors (ERRs) alpha, beta, and gamma are orphan nuclear hormone receptors that share significant homology with the estrogen receptors (ERs) but are not activated by natural estrogens. In contrast, the ERRs display constitutive transcriptional activity in the absence of exogenously added ligand. However, the ERRs bind to the estrogen response element and to the extended half-sites of which a subset can also be recognized by ERalpha, suggesting that ERRs and ERs may control overlapping regulatory pathways. To test this hypothesis, we explored the possibility that ERRs could regulate the expression of the estrogen-inducible pS2 gene, a human breast cancer prognostic marker. Transfection studies show that all of the ERR isoforms can activate the pS2 promoter in a variety of cell types, including breast cancer cell lines. Surprisingly, sequence analysis combined with mutational studies revealed that, in addition to the well-characterized estrogen response element, the presence of a functional extended half-site within the pS2 promoter is also required for complete response to both ER and ERR pathways. We show that ERR transcriptional activity on the pS2 promoter is considerably enhanced in the presence of all three members of the steroid receptor coactivator family but is completely abolished on treatment with the synthetic estrogen diethylstilbestrol, a recently described inhibitor of ERR function. Finally, we demonstrate that ERRalpha is the major isoform expressed in human breast cancer cell lines and that diethylstilbestrol can inhibit the growth of both ER-positive and -negative cell lines. Taken together, these results demonstrate that estrogen-inducible genes such as pS2 can be ERR targets and suggest that pharmacological modulation of ERRalpha activity may have therapeutic value in the treatment of breast cancer.
UI - 21459561
AU - Ray GN; Shahid M; Husain SA
TI - Effect of nitric oxide and malondialdehyde on sister-chromatid exchanges in breast cancer.
SO - Br J Biomed Sci 2001;58(3):169-76
AD - Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Nitric oxide (NO) and malondialdehyde (MDA) play a significant role in DNA damage, sister-chromatid exchanges (SCEs) and carcinogenesis. Here, we determine plasma NO and MDA to evaluate their role in carcinogenesis and their effect on the frequency of SCEs in 45 female breast cancer patients and in 35 age- and sex-matched controls. Plasma NO (P<0.01) and MDA (P<0.001) was significantly higher in the breast cancer group, and a direct correlation were found between plasma NO and MDA concentration and tumour grade. Patients with stage II disease showed the highest levels of both NO and MDA, compared with controls. Simultaneously, SCE frequency per lymphocyte in the breast cancer group was found to be significantly (P<0.001) higher; the greatest increase being found in patients with stage IV disease. Positive correlation was found between SCEs and both NO and MDA in the breast cancer group; however, both NO and MDA production decreased with increasing severity of the disease. Lower NO production in stage IV disease may be due to lower expression of nitric oxide synthase (NOS), further facilitating the production of superoxide anions (O2*-). The reaction between NO and O2*- results in peroxynitrite (OONO-) formation, which works efficiently at the molecular level and may induce higher SCE frequency. This work suggests that further cytogenetic and molecular study is required to provide definite answers for the therapeutic use of NO in breast cancer.