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NCI CANCERLIT^® Search: Breast Cancer, Hereditary - October 2002

National Cancer Institute^®
Last Modified: October 1, 2002

[A study of human breast carcinoma xenografts in nude mice]
Support groups for people carrying a BRCA mutation.
Gene expression in inherited breast cancer.
Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray.
Mutation analysis of the mel-18 gene that shows decreased expression in human breast cancer cell lines.
Management of early-onset breast cancer and BRCA1 or BRCA2 status.
Removal of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts as a measure of DNA repair capacity in lymphoblastoid cell lines from sisters
Transcription and alternative splicing of telomerase reverse transcriptase in benign and malignant breast tumours and in adjacent
Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer.
Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A
Cancer risks in BRCA1 carriers: time for the next generation of studies.
Her-2/neu and INT2 proto-oncogene amplification in malignant breast tumors in relation to reproductive factors and exposure to exogenous
Relationship between X chromosome activation, Barr body frequency and oestrogen receptor status in human breast cancer: a hypothesis.
Cystic disease, family history of breast cancer, and use of oral contraceptives.
UICC Multidisciplinary Project on Breast Cancer: the epidemiology, aetiology and prevention of breast cancer.
[Breast cancer in young women with a history of breast cancer in their mother]
Genetics, biomarkers, and control of breast cancer: a review.
Distinct promoter usage of mdm2 gene in human breast cancer.
A highly polymorphic CA repeat marker at the EBAG9/RCAS1 locus on 8q23 that detected frequent multiplication in breast cancer.
The desmoplastic response to infiltrating breast carcinoma: gene expression at the site of primary invasion and implications for
[Approach of menopause in women at risk for breast cancer]
Women's decisions regarding management of breast cancer risk.
Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy.
Estrogen and Myc negatively regulate expression of the EphA2 tyrosine kinase.
CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.
Peripheral blood c-erbB-2 expression by reverse transcriptase-polymerase chain reaction in breast cancer patients receiving chemotherapy.
Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human
A possible tumor suppressor role of the KLF5 transcription factor in human breast cancer.
Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan.
Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer.
BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
Mutation analysis of the BRCA1 gene in Malaysian breast cancer patients.
Nonovarian pelvic cancers in BRCA1/2 mutation carriers and the BRCAPRO statistical model.
Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study.
Prohibitin 3' untranslated region polymorphism and breast cancer risk in Australian women.
Hereditary breast cancer and possible risk of mammography.
Mammography and hereditary breast cancer.
A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells.
Constitutive expression of the Id-1 promoter in human metastatic breast cancer cells is linked with the loss of NF-1/Rb/HDAC-1 transcription
Molecular characterization of breast cancer cell lines by expression profiling.
Blockade of AP1 transactivation abrogates the abnormal expression of breast cancer-specific gene 1 in breast cancer cells.
Tumor-associated overexpression of the soluble T1-S receptor in lymph node-negative breast cancer.
The hD52 (TPD52) gene is a candidate target gene for events resulting in increased 8q21 copy number in human breast carcinoma.
[Analysis of mutations in genes BRCA1 and BRCA2 among patients with breast and ovarian cancer in northern Portugal and Galicia]
Parent-child factors and their effect on communicating BRCA1/2 test results to children.
Her2 expression in prostatic cancer: a comparison with mammary carcinoma.
Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families.
Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma.
Breast cancer in men.
Summaries for patients. Breast cancer in men.
Expression of Menkes disease gene in mammary carcinoma cells.
Functional mutations of estrogen receptor protein: assay for detection.
[ERBB2/HER2: from molecular to clinical oncology]
Overexpression of insulin-like growth factor II (IGFII) in ZR-75-1 human breast cancer cells: higher threshold levels of receptor (IGFIR) are
Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families.
HMG-I/Y in human breast cancer cell lines.
Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers.
Addressing the support needs of women at high risk for breast cancer: evidence-based care by advanced practice nurses.
BRCA1, C-erbB-2, and H-ras gene expressions in young women with breast cancer. An immunohistochemical study.
Evaluation of numeric alterations of chromosomes 1 and 17 by in situ hybridization in invasive breast carcinoma with clinicopathologic
Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer.
A low-density DNA microarray for analysis of markers in breast cancer.
Hypermethylation and histone deacetylation lead to silencing of the maspin gene in human breast cancer.
The risk of breast cancer associated with dietary lignans differs by CYP17 genotype in women.
[Analysis of the expression of the oncogene c-myc in human breast adenocarcinoma]
A sociobehavioural perspective on genetic testing and counselling for heritable breast, ovarian and colon cancer.
Intron 3 16 bp duplication polymorphism of p53 is associated with an increased risk for breast cancer by the age of 50 years.

1
UI - 11218886
AU - Li Z; Huang X; Li J
TI - [A study of human breast carcinoma xenografts in nude mice]
SO - Zhonghua Yi Xue Za Zhi 2000 Nov;80(11):865-8
AD - Department of Surgery, Clinical School of Oncology, Beijing University, Beijing Institute for Cancer Research, Beijing 100036, China.
OBJECTIVE: To study the spontaneous metastasis and the genetic stability of human breast carcinoma xenografts in nude mice and its micrometastasis. METHODS: The intact tissue of surgical specimens from breast carcinoma were xenografted into nude mice and transplanted from generation to generation. Cells from the xenografts were cultured in vitro and retransplanted into nude mice. Microsatellite DNA in genome of human breast carcinoma, xenotransplanted tumors and metastases in nude mice were analysed at three microsatellite loci. RESULTS: The tumorigenicity of orthotopic xenotransplantation was 88.6%(31/35) with a metastasis rate of 41.9%(13/31). Cells from the xenografts were cultured in vitro successfully, both the take rate of retransplantation into nude mice and the spontaneous lung metastasis rate were 100%(10/10). Microsatellite DNA sequences in genome of the xenotransplanted tumors and metastases in nude mice were identical with that of the original human breast carcinoma at the three microsatellite loci. CONCLUSIONS: The tumorigenicity and metastasis potential can be improved in human breast carcinoma xenograft using the intact fresh tumor tissue and orthotopic graft. The xenotransplanted tumors and their passaged tumors maintained the genetic stability. The detection of microsatellite DNA may discover micrometastasis in the nude mice model.

2
UI - 11584558
AU - Dorval M; Maunsell E; Dugas MJ; Simard J
TI - Support groups for people carrying a BRCA mutation.
SO - CMAJ 2001 Sep 18;165(6):740; discussion 740, 742

3
UI - 11883525
AU - Hedenfalk IA; Ringner M; Trent JM; Borg A
TI - Gene expression in inherited breast cancer.
SO - Adv Cancer Res 2002;84():1-34
AD - Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Large proportions of hereditary breast cancers are due to mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2. Considerable effort has gone into studying the function(s) of these tumor suppressor genes, both in attempts to better understand why individuals with these inherited mutations acquire breast (and ovarian) cancer and to potentially develop better treatment strategies. The advent of tools such as cDNA microarrays has enabled researchers to study global gene expression patterns in, for example, primary tumors, thus providing more comprehensive overviews of tumor development and progression. Our recent study (Hedenfalk et al., 2001) strongly supports the principle that genomic approaches to classification of hereditary breast cancers are possible, and that further studies will likely identify the most significant genes that discriminate between subgroups and may influence prognosis and treatment. A large number of hereditary breast cancer cases cannot be accounted for by mutations in these two genes and are believed to be due to as yet unidentified breast cancer predisposition genes (BRCAx). Subclassification of these non-BRCA1/2 breast cancers using cDNA microarray-based gene expression profiling, followed by linkage analysis and/or investigation of genomic alterations, may help in the recognition of novel breast cancer predisposition loci. To summarize, gene expression-based analysis of hereditary breast cancer can potentially be used for classification purposes, as well as to expand upon our knowledge of differences between different forms of hereditary breast cancer. Initial studies indicate that a patient's genotype does in fact leave an identifiable trace on her/his cancer's gene expression profile.

4
UI - 12196718
AU - Nishizuka I; Ishikawa T; Hamaguchi Y; Kamiyama M; Ichikawa Y; Kadota K;
TI - Miki R; Tomaru Y; Mizuno Y; Tominaga N; Yano R; Goto H; Nitanda H; Togo S; Yasushi Y; Hayashizaki Y; Shimada H Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray.
SO - Breast Cancer 2002;9(1):26-32
AD - Department of Surgery-2, Yokohama City University, School of Medicine, 3-9 Fukuura Kanazawa-ku, Kanagawa 236-0004, Japan.
BACKGROUND: Brain metastases occur in 15% to 30% of breast cancer patients, usually as a late event. The patterns of metastases to different organs are determined by the tumor cell phenotype and interactions between the tumor cells and the organ environment. METHODS: We investigated the gene expression profile occurring in brain metastases from a breast cancer cell line. We used cDNA microarrays to compare patterns of gene expression between the mouse breast cancer cell line Jyg MC (A) and a subline that often metastasis to brain, (B). RESULTS: By Microarray analysis about 350 of 21,000 genes were significantly up-regulated in Jyg MC (B). Many candidate genes that may be associated with the establishment of brain metastasis from breast cancer were included. Interestingly, we found that the expression of astrocyte derived cytokine receptors (IL-6 receptor, TGF-beta receptor and IGF receptor) were significantly increased in Jyg MC (B) cells. These results were confirmed by RT-PCR. CONCLUSIONS: These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases from breast cancer cells.

5
UI - 12196719
AU - Matsuo F; Yano K; Saito H; Morotomi K; Kato M; Yoshimoto M; Kasumi F;
TI - Akiyama F; Sakamoto G; Miki Y Mutation analysis of the mel-18 gene that shows decreased expression in human breast cancer cell lines.
SO - Breast Cancer 2002;9(1):33-8
AD - Department of Molecular Diagnosis, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
BACKGROUND: Mammalian mel-18 is a member of the polycomb group, and it acts as a transcriptional repressor with DNA binding activity. Murine mel-18 negatively regulates the cell cycle through the c-myc/cdc25 cascade, and mice haploinsufficient for mel-18 develop mammary gland tumors. In addition, the human homolog of mel-18 is located at 17q, on which candidate tumor suppressor genes for breast cancer have been suggested for a long time. These observations indicate that the mel-18 gene may be a tumor suppressor gene for breast cancer. To investigate this possibility, we examined the expression of mel-18 mRNA in human breast cancer cell lines and searched for mel-18 gene mutations in sporadic and familial breast cancers. METHODS: The expression of mel-18 mRNA was examined in five breast cancer cell lines by RT-PCR, and somatic and germline mutations of the mel-18 gene were analyzed by the PCR-SSCP and sequence methods in 48 sporadic breast cancers, including 16 cases with loss of heterozygosity (LOH) at the mel-18 locus, and in 23 cases from 18 breast cancer families, respectively. RESULTS: We found that most cell lines examined here showed decreased expression of mel-18 mRNA, however, no alteration other than a single nucleotide change that did not lead to amino acid alteration in one patient was identified. CONCLUSION: Our results reveal that mel-18 gene mutations are exceedingly rare in human breast cancers, and a reduction of mel-18 expression in human breast cancer cell lines would support a role for mel-18 haploinsufficiency in breast carcinogenesis.

6
UI - 12241952
AU - Vaidya JS; Baum M
TI - Management of early-onset breast cancer and BRCA1 or BRCA2 status.
SO - Lancet 2002 Aug 24;360(9333):640; discussion 640-1

7
UI - 12203401
AU - Motykiewicz G; Faraglia B; Wang LW; Terry MB; Senie RT; Santella RM
TI - Removal of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts as a measure of DNA repair capacity in lymphoblastoid cell lines from sisters discordant for breast cancer.
SO - Environ Mol Mutagen 2002;40(2):93-100
AD - Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA. gm54@columbia.edu
The mutagen sensitivity assay is one of the approaches used to investigate individual DNA repair capacity. This method is based on the premise that after in vitro treatment with a test mutagen, DNA from subjects with defective repair will be more damaged than DNA from those with an efficient repair system. However, very little is known about unmeasured processes that occur between cell treatment and final assessment of DNA damage. To develop a more precise assay, we modified the traditional mutagen sensitivity assay to also include measurement of DNA damage after culturing cells in the absence of mutagen. First, we treated apparently normal and xeroderma pigmentosum lymphoblastoid cell lines with various doses of benzo(a)pyrene diol epoxide (BPDE) and harvested cells at different time points. A polyclonal antiserum against BPDE-DNA was used to quantitate levels of adducts by immunoslot-blot and immunohistochemistry. Selected conditions included treatment with 10 microM BPDE, a 4-hr culture in mutagen-free medium, and immunohistochemical measurement of BPDE-DNA adducts. The method was then applied in a pilot study to 50 lymphoblastoid lines from sisters discordant for breast cancer. There was no significant difference between cases and controls in the level of BPDE-DNA adducts in lymphoblasts harvested immediately after BPDE treatment. However, after a 4-hr culture in mutagen-free medium, the level of adducts was significantly higher (P = 0.006) among cases than in controls. There was a two-fold increase in mean adduct removal in lines from nonaffected as compared to affected sisters (44% and 22% decrease, respectively). DNA repair capacity was predictive of case status (P = 0.04) in logistic regression analysis. This method, which can be easily applied to large numbers of samples, should be useful in studies to investigate the role of DNA repair in cancer risk. Copyright 2002 Wiley-Liss, Inc.

8
UI - 12210061
AU - Zaffaroni N; Della Porta C; Villa R; Botti C; Buglioni S; Mottolese M;
TI - Grazia Daidone M Transcription and alternative splicing of telomerase reverse transcriptase in benign and malignant breast tumours and in adjacent mammary glandular tissues: implications for telomerase activity.
SO - J Pathol 2002 Sep;198(1):37-46
AD - Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. zaffaroni@istitutotumori.mi.it
Telomerase activity was determined in 15 breast cancers, 24 benign breast lesions, and 36 breast tissues adjacent to benign or malignant tumours. A positive TRAP (telomeric repeat amplification protocol) signal was detected in 67% of carcinomas and 29% of benign tumours. In five of ten cases, non-invaded breast tissues adjacent to telomerase-positive carcinomas also displayed telomerase activity. Conversely, in peritumoural specimens adjacent to benign lesions, telomerase activity was never detected. To investigate the regulatory mechanisms of telomerase activity in breast tissues, the expression of telomerase subunits was assessed, as well as the presence of alternatively spliced variants of human telomerase reverse transcriptase (hTERT). The presence of the hTERT full-length transcript appeared necessary for telomerase activity in breast carcinomas. Specifically, all telomerase-positive carcinomas expressed the hTERT full-length message, together with different combinations of alternatively spliced variants, whereas in telomerase-negative cancers, the hTERT full-length transcript was not detectable, or its abundance was markedly lower than that of alternatively spliced variants. Results obtained in benign tumours and normal tissues surrounding carcinomas instead showed that the presence of hTERT full-length transcript was not sufficient to determine telomerase activity. These findings suggest that in non-neoplastic tissues there are other mechanisms that suppress telomerase activity downstream from hTERT transcription and mRNA splicing and that such mechanisms have been lost during neoplastic transformation. Copyright 2002 John Wiley & Sons, Ltd.

9
UI - 12241875
AU - Klein CA; Blankenstein TJ; Schmidt-Kittler O; Petronio M; Polzer B;
TI - Stoecklein NH; Riethmuller G Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer.
SO - Lancet 2002 Aug 31;360(9334):683-9
AD - Institut fur Immunologie, Ludwig-Maximilians-Universitat Munchen, D-80336 Munchen, Germany. christoph.klein@ifi.med.uni-muenchen.de
BACKGROUND: Because cancer patients with small tumours often relapse despite local and systemic treatment, we investigated the genetic variation of the precursors of distant metastasis at the stage of minimal residual disease. Disseminated tumour cells can be detected by epithelial markers in mesenchymal tissues and represent targets for adjuvant therapies. METHODS: We screened 525 bone-marrow, blood, and lymph-node samples from 474 patients with breast, prostate, and gastrointestinal cancers for single disseminated cancer cells by immunocytochemistry with epithelial-specific markers. 71 (14%) of the samples contained two or more tumour cells whose genomic organisation we studied by single cell genomic hybridisation. In addition, we tested whether TP53 was mutated. Hierarchical clustering algorithms were used to determine the degree of clonal relatedness of sister cells that were isolated from individual patients. FINDINGS: Irrespective of cancer type, we saw an unexpectedly high genetic divergence in minimal residual cancer, particularly at the level of chromosomal imbalances. Although few disseminated cells harboured TP53 mutations at this stage of disease, we also saw microheterogeneity of the TP53 genotype. The genetic heterogeneity was strikingly reduced with the emergence of clinically evident metastasis. INTERPRETATION: Although the heterogeneity of primary tumours has long been known, we show here that early disseminated cancer cells are genomically very unstable as well. Selection of clonally expanding cells leading to metastasis seems to occur after dissemination has taken place. Therefore, adjuvant therapies are confronted with an extremely large reservoir of variant cells from which resistant tumour cells can be selected.

10
UI - 12240546
AU - Thames HD; Petersen C; Petersen S; Nieder C; Baumann M
TI - Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A treatment-specific overview of the clinical data.
SO - Strahlenther Onkol 2002 Aug;178(8):411-21
AD - Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
BACKGROUND: The aim was to ascertain whether many hundreds of clinical reports over the last decade are consistent with the prediction of a poorer outcome in cancer patients with p53 abnormalities treated with cytotoxic drugs and radiation. MATERIAL AND METHOD: There are 301 studies on the influence of p53 overexpression published through summer 2000, in which chemotherapy or radiotherapy was used alone or in combination with surgery. From 45 reports meeting stringent selection rules, comparison groups are identified in whom the same measure of outcome was reported for the same treatment applied to the same tumor, with results corrected for important prognostic factors. Metaanalysis techniques are then applied to the comparison groups. Attention was limited to reports using immunohistochemical techniques, to form comparison groups of sufficient size. RESULTS: Four comparison groups were identified by treatment and endpoint: 1) Stage I-III breast cancer (surgery and chemotherapy, disease-free survival, seven studies); 2) stage I-III breast cancer (surgery and chemotherapy, overall survival, six studies); 3) stage II-IV head and neck cancer (radiotherapy and chemotherapy, overall survival, five studies); 4) FIGO I-IV ovarian cancer (surgery and chemotherapy, overall survival, six studies). In the breast (disease-free survival) and ovarian (overall survival) comparison groups, the hazard ratio for a deleterious effect of p53 overexpression was significant or marginally significant, depending on assumed ranges for unreported hazard ratios in non-significant studies. CONCLUSIONS: Despite the many caveats related to metaanalysis applied to retrospective data, high variability of immunohistochemical technique, etc., a nearly significant negative effect of p53 overexpression on outcome of treatment with cytotoxic drugs and radiation emerges in the few studies where heterogeneity can be sufficiently reduced or accounted for.

11
UI - 12237273
AU - Gruber SB; Petersen GM
TI - Cancer risks in BRCA1 carriers: time for the next generation of studies.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1344-5

12
UI - 1920494
AU - Olsson H; Borg A; Ferno M; Ranstam J; Sigurdsson H
TI - Her-2/neu and INT2 proto-oncogene amplification in malignant breast tumors in relation to reproductive factors and exposure to exogenous hormones.
SO - J Natl Cancer Inst 1991 Oct 16;83(20):1483-7
AD - Department of Oncology, University Hospital, Lund, Sweden.
In previous studies in southern Sweden, early use of oral contraceptives has been found to be accompanied by an increased risk of developing premenopausal breast cancer, and the tumors developing in these patients have shown a more aggressive behavior. In the present study, amplification of the proto-oncogenes Her-2/neu (also known as ERBB2) and INT2 was studied in primary tumor specimens from 72 premenopausal women and was related to starting age of oral contraceptive use and other reproductive risk factors. Amplification of Her-2/neu was more common among early oral contraceptive users (i.e., those starting at less than or equal to 20 years of age) than among nonusers or late users (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-16.7), whereas INT2 amplification did not differ significantly among those groups (OR, 0.9; 95% CI, 0.1-5.0). The likelihood of INT2 amplification was greater among users of progestins and those with a history of abortions before the first full-term pregnancy (OR, 9.0; 95% CI, 1.3-51.7; and OR, 18.6; 95% CI, 2.2-165.8, respectively). No significant relationships were found between proto-oncogene amplification and the variables of parity, age at first full-term pregnancy, or late abortion. The increased ORs persisted after adjustment for age at diagnosis and other risk factors. The findings suggest that the higher rate of Her-2/neu amplification among early oral contraceptive users is an effect of the oral contraceptive use per se rather than of the relative youth of the users. Moreover, the relationship between progestin use and early abortion and amplification of the INT2 gene is biologically plausible.

13
UI - 7350552
AU - Smethurst M; Bishun NP; Williams DC
TI - Relationship between X chromosome activation, Barr body frequency and oestrogen receptor status in human breast cancer: a hypothesis.
SO - Oncology 1980;37(1):30-2
Current evidence indicates an association between oestrogens, sex chromatin frequency and X chromosome activation in relation to the activity of the enzyme glucose-6-phosphate dehydrogenase. We suggest that a similar association might apply to control the level of oestradiol receptors in breast tumours and present information supporting this hypothesis.

14
UI - 7349817
AU - Vakil DV; Elinson L; Morgan RW
TI - Cystic disease, family history of breast cancer, and use of oral contraceptives.
SO - Cancer Detect Prev 1981;4(1-4):511-5
Epidemiologic studies show a lower frequency of fibrocystic breast disease among users of oral contraceptives than among women who have never used them. Family history of breast cancer appears to be more common among benign breast disease patients than among their controls. To determine the use of oral contraceptives and the presence of family history of breast cancer, information was obtained from 211 cystic cases and their matched controls from the metropolitan Toronto area. Cystic cases compared to controls had a higher proportion of women with a family history of breast cancer (21% vs 15%). For both a positive and negative family history of breast cancer, as well as for all women combined, the mean duration of oral contraceptive use was lower for cystic cases than for controls. The odds ratio for oral contraceptive use according to family history of breast cancer for cystic cases and controls was 0.42 and 0.81 respectively. The possibility that a woman is more protected against benign breast disease by using oral contraceptives if she has a family history of breast cancer deserves more attention in future investigations on the long-term effects of birth control pills.

15
UI - 3455923
AU - Miller AB; Bulbrook RD
TI - UICC Multidisciplinary Project on Breast Cancer: the epidemiology, aetiology and prevention of breast cancer.
SO - Int J Cancer 1986 Feb 15;37(2):173-7

16
UI - 3824281
AU - Lund E
TI - [Breast cancer in young women with a history of breast cancer in their mother]
SO - Tidsskr Nor Laegeforen 1987 Jan 10;107(1):12-3

17
UI - 6380704
AU - Lynch HT; Albano WA; Heieck JJ; Mulcahy GM; Lynch JF; Layton MA; Danes
TI - BS Genetics, biomarkers, and control of breast cancer: a review.
SO - Cancer Genet Cytogenet 1984 Sep;13(1):43-92
More has been written about the epidemiology of breast cancer than possibly any other form of cancer affecting mankind. However, in the face of this intense interest, only a paucity of attention has been given to the role of genetics in its etiology. This review represents an attempt by the investigators to provide a comprehensive coverage of hereditary breast cancer. Included are pertinent endogeneous and exogeneous risk factors, which in certain circumstances, may significantly influence the role of primary genetic factors. Hereditary breast cancer is heterogeneous. When discussing the subject, therefore, one must be precise relevant to the particular heterogeneous form of concern, based on differing tumor associations. It is probably not appropriate to discuss "hereditary breast cancer" without qualification of the specific hereditary breast cancer syndrome of concern; i.e., the SBLA syndrome, breast/ovarian cancer syndrome, and others. This reasoning also applies to attempts at linking biomarkers to hereditary breast cancer. Finally, in addition to ongoing discussions on the cardinal principles that associate with hereditary forms of breast cancer, its frequency, and new developments in biomarkers, we have provided surveillance/management programs that embrace those facets of the natural history of this disease.

18
UI - 11956627
AU - Okumura N; Saji S; Eguchi H; Nakashima S; Saji S; Hayashi S
TI - Distinct promoter usage of mdm2 gene in human breast cancer.
SO - Oncol Rep 2002 May-Jun;9(3):557-63
AD - Second Department of Surgery, Gifu University School of Medicine, Gifu 500-8705, Japan. n-okumura@umin.ac.jp
Human breast cancers, especially estrogen receptor alpha (ER(alpha))-positive ones, often overexpress the oncoprotein MDM2 without mdm2 gene amplification. The mdm2 gene is transcribed into two different mRNAs, namely L-mdm2 and S-mdm2, which are generated from promoters P1 (constitutive) and P2 (regulated by tumor suppressor p53), respectively. To cast light on the mechanisms of MDM2 overexpression, we measured the expression levels of these mdm2 mRNAs using RT-PCR analysis in three human breast cancer cell lines and 15 breast cancer samples obtained from surgery. ER(alpha)-positive MCF-7 cells, which possess wild-type p53, displayed dominant expression of S-mdm2. In contrast, two other cell lines with mutant p53, T47-D (ER(alpha)-positive) and MDA-MB-231 (ER(alpha)-negative), showed almost equivalent expression of L-mdm2 and S-mdm2. Treatment of 17beta-estradiol (E2) significantly enhanced the expression of S-mdm2 but not that of L-mdm2 in MCF-7. Among 6 breast cancer samples regarded as ER(alpha)-positive with wild-type p53, 5 samples showed increased expression of S-mdm2. Expression of S-mdm2 was stimulated in 2 ER(alpha)-positive samples with mutant p53. In contrast, 4 of 5 samples which express mutant p53 without ER(alpha) showed poor expression of S-mdm2. There is a tendency that ER(alpha)-positive breast cancers with wild-type p53 preferably use P2 promoter for the expression of mdm2, possibly through E2-induced accumulation of p53. However, wild-type p53 and ER(alpha) are not necessarily enough for the utilization of S-mdm2. Tumors with mutant p53 also showed expression of S-mdm2 in some cases. These results strongly suggest that other factor(s) is also implicated in the promoter usage of mdm2 gene in human breast cancer tissues.

19
UI - 12160478
AU - Tsuneizumi M; Nagai H; Harada H; Kazui T; Emi M
TI - A highly polymorphic CA repeat marker at the EBAG9/RCAS1 locus on 8q23 that detected frequent multiplication in breast cancer.
SO - Ann Hum Biol 2002 Jul-Aug;29(4):457-60
AD - Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Nakahara-ku, Kawasaki, 211-8533, Japan.
BACKGROUND: Cloning of CpG binding sites in the human genome initially identified EBAG9 (estrogen receptor-binding fragment-associated gene 9), an estrogen-responsive gene mapped to chromosome 8q23. Its product was later found to be identical to RCAS1 (receptor-binding cancer antigen expressed on SiSo cells 1). RCAS1 was recently described as a cancer-surface antigen, implicated in immune escape in a human uterine adenocarcinoma cell line, which turned out to be identical to the EBAG9 molecule. AIM: The study seeks to isolate a highly polymorphic dinucleotide repeat at this locus that detects frequent multiplication of the EBAG9/RCAS1 gene. Subject and methods: A fragment containing CA repeat was identified by Southern blotting of bacterial artificial chromosome (BAC) clone containing the EBAG9/RCAS1 gene digested by Hae III, Sau 3A or Rsa I with (GT)20 probe, subcloned and sequenced. RESULTS: We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the EBAG9/RCAS1 gene located at 8q23. High heterozygosity (0.859) makes this polymorphism a useful marker in genetic studies. This marker detected frequent multiplication of the EBAG9/RCAS1 gene in primary breast cancers (27 of 129 tumours). CONCLUSION: This marker is useful for detecting frequent multiplication of the EBAG9/RCAS1 gene in primary breast cancers and other cancers.

20
UI - 12235006
AU - Iacobuzio-Donahue CA; Argani P; Hempen PM; Jones J; Kern SE
TI - The desmoplastic response to infiltrating breast carcinoma: gene expression at the site of primary invasion and implications for comparisons between tumor types.
SO - Cancer Res 2002 Sep 15;62(18):5351-7
AD - Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
The gene expression patterns of desmoplasia are becoming exposed through the application of global gene expression technologies such as cDNA microarrays or serial analysis of gene expression (SAGE). These patterns represent the sum of the many cellular components of the host stromal response to an infiltrating carcinoma. In studies of human neoplasms, it would be useful to identify those prototypical genes that characteristically indicate the recognizable forms of the responses to individual tumor types. Such genes may offer clues to better understand the process of invasion itself, the interactions between tumor and host cells, and tumor-specific differences in invasion. We used SAGE-defined genes and in situ transcript labeling to characterize the desmoplastic stroma induced by infiltrating ductal carcinomas of the breast. Principal component analysis identified 103 SAGE tags as specific for invasive breast carcinomas, in comparison with in situ duct carcinomas or normal breast epithelium. Of these, 68 tags corresponded to known genes. Six of the 68 genes from this breast cancer "invasion-specific" cluster were further characterized by in situ hybridization to breast cancer tissues. Results of in situ hybridization demonstrated that each gene was expressed within one of five distinct regions of the invasive tumors (neoplastic epithelium; angioendothelium; inflammatory, panstromal, and juxtatumoral stroma), reflecting a defined architectural structure to the transcriptome of invasive breast cancers. Two of these 6 genes were specifically expressed by the stromal cells within the invasive carcinoma; however, 1 (collagen 1alpha1) was expressed throughout the stromal response (panstromal expression), whereas the second (osteonectin) was specifically expressed within the juxtatumoral stromal cells, indicating a critical "regionality" of gene expression within the stromal response itself. A comparison of the gene expression profiles of the juxtatumoral stroma in breast and pancreatic carcinomas indicated important differences between the two, suggesting tumor-specific or organ-specific differences in the desmoplastic responses. Some of the genes presented are novel markers of the invasive process, imply communication at the host/tumor interface, and suggest potential therapeutic targets.

21
UI - 11910878
AU - This P; Cormier C
TI - [Approach of menopause in women at risk for breast cancer]
SO - Gynecol Obstet Fertil 2002 Feb;30(2):101-13
AD - Service de chirurgie a orientation senologique, Institut Curie, 75231 Paris, France. pthis@ch-versailles.fr
The small but significant increase in risk of discovering breast cancer in women with hormone replacement therapy and the recent discussion of coronary benefit of this treatment have led many authors to insist on the necessity to evaluate the benefit/risks ratio before administration. This evaluation is particularly important for women that are already at high risk of breast cancer because of some genetic predisposition, family history or some benign breast diseases. In these cases, it is important to evaluate the absolute risk of breast cancer, to define the patient's needs more precisely, to specify menopausal symptoms; it is also important to evaluate the risk of osteoporosis, to review the various therapeutic possibilities, which are not only estrogen/progestin treatments (there are alternative treatments), and to give the patients honest information. Before obtaining the results of current trials, we are proposing here a pragmatic attitude and a decision algorithm to adopt a therapeutic attitude more easily which will be decided together by both patients and their physicians.

22
UI - 12219430
AU - MacDonald DJ
TI - Women's decisions regarding management of breast cancer risk.
SO - Medsurg Nurs 2002 Aug;11(4):183-6
AD - City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Twenty-three unaffected women with a family history of breast or ovarian cancer participated in a study to ascertain their cancer-related concerns, beliefs, and preferences for risk management. Their perceptions related to breast cancer risk management options have implications for practicing nurses.

23
UI - 12243922
AU - Bertheau P; Plassa F; Espie M; Turpin E; de Roquancourt A; Marty M;
TI - Lerebours F; Beuzard Y; Janin A; de The H Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy.
SO - Lancet 2002 Sep 14;360(9336):852-4
AD - Service de Pathologie and INSERM ERM 0220, Hopital Saint-Louis, 1 Ave C, Vellefaux, 75475 Paris, Cedex 10, France.
TP53 activation by genotoxic drugs can induce apoptosis or cell-cycle arrest. Thus, whether the gene is mutated or wild type could affect the response of a tumour to chemotherapy. Clinical data are unclear, possibly as a result of heterogeneity of tumours, drugs, methods of assessing response, or TP53 status. We studied 50 non-inflammatory, locally advanced breast cancers that had been treated with high doses of a combination of epirubicin and cyclophosphamide. We noted eight complete responses, which all occurred in the 14 patients with tumours containing mutated TP53 (p<0.0001). In high-grade, advanced breast cancers, inactivation of the TP53 pathway could greatly improve the response to this chemotherapy regimen.

24
UI - 11968011
AU - Zelinski DP; Zantek ND; Walker-Daniels J; Peters MA; Taparowsky EJ;
TI - Kinch MS Estrogen and Myc negatively regulate expression of the EphA2 tyrosine kinase.
SO - J Cell Biochem 2002;85(4):714-20
AD - Department of Basic Medical Sciences, Purdue University Cancer Center, West Lafayette, Indiana 47907, USA.
Estrogen receptor and c-Myc are frequently overexpressed during breast cancer progression but are downregulated in many aggressive forms of the disease. High levels of the EphA2 tyrosine kinase are consistently found in the most aggressive breast cancer cells, and EphA2 overexpression can increase metastatic potential. We demonstrate, herein, that estrogen and Myc negatively regulate EphA2 expression in mammary epithelial cells. These data reveal EphA2 as a downstream target of estrogen and Myc and suggest a mechanism by which estrogen and Myc may regulate breast cancer. Copyright 2002 Wiley-Liss, Inc.

25
UI - 12019214
AU - Nathanson KL; Shugart YY; Omaruddin R; Szabo C; Goldgar D; Rebbeck TR;
TI - Weber BL CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.
SO - Hum Mol Genet 2002 May 15;11(11):1327-32
AD - Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Women with germline mutations in BRCA1 have a greatly elevated risk of breast and ovarian cancer. However, considerable variation in the degree of breast cancer risk associated with a BRCA1 mutation has been observed, suggesting that modifiers of BRCA1 penetrance may exist. We hypothesized that the modifier genes might be located in regions of allelic imbalance in the tumors of BRCA1 mutation carriers, as have been reported on chromosomes 4p, 4q and 5q. In order to determine whether novel genetic modifiers of BRCA1-associated breast cancer penetrance in these regions exist, we used non-parametric linkage analysis methods to determine whether allele sharing of chromosomes 4p, 4q and 5q was observed preferentially within BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, we observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). These results suggest the presence of one or more genes on chromosome 5q33-34 that modify breast cancer risk in BRCA1 mutation carriers. The approach described here may be utilized to identify penetrance modifiers in other autosomal dominant syndromes.

26
UI - 12196278
AU - Fonseca FL; Soares HP; Manhani AR; Bendit I; Novaes M; Zatta SM; Arias
TI - V; Pinhal MA; Weinschenker P; del Giglio A Peripheral blood c-erbB-2 expression by reverse transcriptase-polymerase chain reaction in breast cancer patients receiving chemotherapy.
SO - Clin Breast Cancer 2002 Aug;3(3):201-5
AD - ABC Foundation Medical School, Sao Paulo, Brazil.
Minimal residual disease (MRD) evaluation in breast cancer patients is a promising tool to improve current staging procedures. In a previous work employing a CK-19-based reverse transcriptase-polymerase chain reaction (RT-PCR) technique for MRD detection, we identified a group of women who exhibited persistent negativity for this assay and for whom this technique was considered noninformative. In order to improve the yield of MRD detection in these patients, we evaluated the usefulness of RT-PCR detection of c-erbB-2 expression. We were able to detect up to 1 MCF-7 cell (positive for c-erbB-2 expression) in a mixture of 1,000,000 CCRF-CEM cells (negative for c-erbB-2 expression). We evaluated the specificity of this technique in the peripheral-blood mononuclear cells (PBMCs) of 20 healthy women and found that 2 of these women were positive for c-erbB-2 expression. In the PBMCs of a group of 16 women with breast cancer, 25% of the samples were positive for c-erbB-2 expression before chemotherapy. Except for race (P = 0.017), no other significant correlations were found, including c-erbB-2 expression in the primary tumor by immunoperoxidase. Interestingly, in the subgroup of 6 patients for whom this technique was informative, we found that 80% of the samples obtained while on chemotherapy were negative compared to only 10% obtained off treatment (P = 0.017). Additionally, 2 patients for whom CK-19 expression was noninformative had at least 1 c-erbB-2-positive sample. We conclude that this technique might be useful for MRD detection in breast cancer patients, but further studies are necessary to confirm our findings.

27
UI - 12216067
AU - Stephenson JM; Banerjee S; Saxena NK; Cherian R; Banerjee SK
TI - Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: a possible marker for the progression of breast cancer.
SO - Int J Cancer 2002 Oct 10;101(5):409-14
AD - Cancer Research Unit, V.A. Medical Center, and Department of Internal Medicine, Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, MO, USA.
The expression and distribution of neuropilin-1 (NRP-1) was examined in the samples of normal human breast tissues and in non-neoplastic and neoplastic areas of breast tissue removed for carcinoma using RT-PCR as well as conventional and tissue microarrays immunohistochemical analyses. The NRP-1 mRNA expression was significantly higher in neoplastic tissues as compared to normal breast samples. Immunohistochemically, the myoepithelial cells of the mammary ducts and lobules display positive reactions for NRP-1, whereas the inner ductal and lobular epithelial cell layers failed to react. The myoepithelial cells of ducts and lobules in both neoplastic and non-neoplastic tissue specimens displayed a stronger positive reaction for NRP-1 than those in the normal breast. A positive reaction for NRP-1, but with a gradual reduction in intensity, was observed in the myoepithelial cells of ducts with atypical epithelial hyperplasia and ductal carcinoma in situ (DCIS). The reaction was undetected or minimally detected in the areas of invasive carcinoma. NRP-1 positive immunolabeling was also localized in the vascular smooth muscle cells and in some endothelial cells of the blood vessels in normal, non-neoplastic and neoplastic breast tissue samples. In areas of breast carcinoma, NRP-1 immunolabeling was more prominent in both vascular smooth muscle cells and in some endothelial cells than in similar cells in normal breast. The specificity of the newly developed antibody for NRP-1 was confirmed by in situ hybridization with DIG-labeled PCR generated probe. These results suggest that NRP-1 may be a multiple function protein in human breast and may be involved in the induction of local invasiveness of neoplasia and angiogenesis and have direct relevance to the progression of breast cancer. Copyright 2002 Wiley-Liss, Inc.

28
UI - 12242654
AU - Chen C; Bhalala HV; Qiao H; Dong JT
TI - A possible tumor suppressor role of the KLF5 transcription factor in human breast cancer.
SO - Oncogene 2002 Sep 26;21(43):6567-72
AD - Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, VA 22908, USA.
The 13q21 tumor suppressor locus, as defined by chromosomal deletion, harbors the KLF5 transcription factor which may have tumor suppressor function. To investigate whether KLF5 plays a role in breast cancer, we evaluated all genes and/or expressed sequence tags (ESTs) within a 3.3 Mb common region of deletion at 13q21. Of these, only KLF5 mRNA was expressed at high levels in non-neoplastic breast epithelial cells and in normal human mammary tissue, but at lower levels in various breast cancer cell lines. Using the real time TaqMan PCR assay, hemizygous deletion at KLF5 was detected in 13 out of 30, or 43% of breast cancer cell lines tested, and various degrees of loss of expression were detected in 21 out of 30, or 70% of these cell lines. Each of the cases with hemizygous deletion also exhibited loss of KLF5 expression, suggesting that loss of expression can result from chromosomal deletion, and that KLF5 may undergo haploinsufficiency during carcinogenesis. Only one of the 30 breast cancer cell lines tested exhibited a mutation in KLF5, and neither promoter methylation nor homozygous deletion was detected in any of the cell lines. In contrast, loss of heterozygosity (LOH) was frequently detected at KLF5. Re-expression of wild-type KLF5 in T-47D breast cancer cells significantly inhibited colony formation in these cells. Of the KLF5-transfected clones that did form colonies, none were found to express KLF5 mRNA. These findings suggest that loss of function by deletion and/or loss of expression frequently occurs at KLF5, and KLF5 suppresses tumor cell growth in breast cancer.

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