National Cancer Institute®
Last Modified: July 1, 2002
UI - 12032322
AU - Welcsh PL; Lee MK; Gonzalez-Hernandez RM; Black DJ; Mahadevappa M;
TI - Swisher EM; Warrington JA; King MC BRCA1 transcriptionally regulates genes involved in breast tumorigenesis.
SO - Proc Natl Acad Sci U S A 2002 May 28;99(11):7560-5
AD - Department of Medicine and Genome Sciences, University of Washington, Health Sciences Room K-160, Seattle, WA 98195-7720, USA.
Loss of function of BRCA1 caused by inherited mutation and tissue-specific somatic mutation leads to breast and ovarian cancer. Nearly all BRCA1 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain, suggesting that transcriptional regulation is a critical function of the wild-type gene. The purpose of this project was to determine whether there is a link between the role of BRCA1 in transcriptional regulation and its role in tumor suppression. We developed a cell line (in which BRCA1 can be induced) and used microarray analysis to compare transcription profiles of epithelial cells with low endogenous levels of BRCA1 vs. transcription profiles of cells with 2-4-fold higher induced levels of expression of BRCA1. At these levels of expression, BRCA1 did not induce apoptosis. Undirected cluster analysis of six paired experiments revealed 373 genes, the expression of which was altered significantly and consistently by BRCA1 induction. Expression of 62 genes was altered more than 2-fold. BRCA1-regulated genes associated with breast tumorigenesis included the estrogen-responsive genes MYC and cyclin D1, which are overexpressed in many breast tumors; STAT1 and JAK1, key components of the cytokine signal transduction pathway; the extracellular matrix protein laminin 3A; ID4, an inhibitor of DNA-binding transcriptional activators, which in turn negatively regulates BRCA1 expression; and the prohormone stanniocalcin, expression of which is lost in breast tumor cells. Coordinated expression of BRCA1 with ID4 and with stanniocalcin was confirmed in primary breast and ovarian tumors.
UI - 12045150
AU - Cozma D; Lukes L; Rouse J; Qiu TH; Liu ET; Hunter KW
TI - A bioinformatics-based strategy identifies c-Myc and Cdc25A as candidates for the Apmt mammary tumor latency modifiers.
SO - Genome Res 2002 Jun;12(6):969-75
AD - Laboratory of Population Genetics, Medicine Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892, USA.
The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
UI - 11933265
AU - Truong K; Vielh P; Guilly MN; Klijanienko J; Sastre-Garau X; Soussaline
TI - F; Dutrillaux B; Malfoy B Quantitative FISH analysis on interphase nuclei may improve diagnosis of DNA diploid breast cancers.
SO - Diagn Cytopathol 2002 Apr;26(4):213-6
AD - Cytogenetique moleculaire et Oncologie, Unite Mixte de Recherche 147, Centre National de Recherche Scientifique-Institut Curie, Paris, France. email@example.com
The detection of DNA aneuploid cells using flow cytometry is an indication for the presence of tumor cells, but when DNA diploid cells are found in 25-33% of the cases, the diagnostic and prognostic significance of DNA ploidy is more limited. We analyzed interphase nuclei after in situ hybridization and using image cytometry on 50 breast tumors with diploid DNA content to investigate whether early chromosome rearrangements were detectable and if their occurrence was clinically significant. Imbalances between the two arms of chromosome 1 were found in 55% of the cases and values ranged from 1.5-3.0. Comparison with histological data showed that Grade I tumors mainly have imbalances (67%) and that Grade III tumors were mainly without the imbalance (67%), whereas Grade II tumors were intermediate (50% imbalance). These data suggest that the diagnosis of DNA diploid cases may be improved by using interphase FISH. In addition, the data also indicates that early breast tumors may have different genetic origins, which is important in the comprehension of tumor malignancy in early stages, especially for preinvasive lesions. Copyright 2002 Wiley-Liss, Inc.
UI - 12037031
AU - Megha T; Ferrari F; Benvenuto A; Bellan C; Lalinga AV; Lazzi S;
TI - Bartolommei S; Cevenini G; Leoncini L; Tosi P p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin.
SO - J Clin Pathol 2002 Jun;55(6):461-6
AD - Institute of Pathologic Anatomy and Histology, University of Siena, 53100, Italy.
AIM: Several studies have investigated the expression of the cytokeratins (CKs), vimentin, the epithelial growth factor receptor (EGFR), the oestrogen receptor (ER), and the progesterone receptor (PgR), in breast cancer, but no study has directly compared p53 mutations with these phenotypic and differentiation markers in the same case. The present study was designed to provide some of this information. METHODS: The expression of the p53 and bcl-2 proteins was evaluated by immunohistochemistry in relation to phenotypic characteristics and cellular kinetic parameters (mitotic index and apoptotic index) in 37 cases of ductal carcinoma in situ (DCIS) and 27 cases of infiltrating ductal carcinoma (IDC) of the breast. In addition, p53 gene mutation was examined by polymerase chain reaction single strand conformation polymorphism analysis (SSCP). RESULTS: Thirteen cases (eight DCIS and five IDC) showed expression of CK8, CK14, CK18, vimentin, and EGFR, consistent with a stem cell phenotype, whereas 44 cases (27 DCIS and 17 IDC) showed expression of CK8 and CK1, weak or negative expression of CK18, but were negative for vimentin and EGFR, consistent with a luminal cell phenotype. DCIS and IDC cases with a stem cell phenotype were ER/PgR negative and intermediately or poorly differentiated. In contrast, the cases with luminal cell phenotype were ER/PgR positive and well or intermediately differentiated. In addition, intermediately or poorly differentiated cases with a stem cell phenotype showed higher proliferative activity (per cent of MIB-l positive cells) than did intermediately or well differentiated cases with a luminal cell phenotype. Both DCIS and IDC cases with a stem cell phenotype were p53 positive and bcl-2 negative by immunohistochemistry. In IDC, p53 expression was associated with a reduction of both mitotic index and apoptotic index compared with DCIS. Most of the tumours showing a more differentiated phenotype (luminal) were p53 negative and bcl-2 positive. In these cases, cell kinetic parameters increased from DCIS to IDC. These data suggest the existence of subsets of DCIS and IDC that, because of their phenotypic characteristics, could be derived from subpopulations of normal breast cells having different control mechanisms of cell proliferation and neoplastic progression. CONCLUSIONS: These results are compatible with the hypothesis that the phenotype of the cell of origin constrains both tumour phenotype and the choice of genetic events; however, the occurrence of p53 mutants by chance during neoplastic transformation cannot be excluded.
UI - 12061481
AU - Meiser B; Halliday JL
TI - What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review.
SO - Soc Sci Med 2002 May;54(10):1463-70
AD - Department of Psychological Medicine, Royal North Shore Hospital, St Leonard, NSW, Sydney, Australia. firstname.lastname@example.org
Meta-analytic methods were used to determine the impact of genetic counselling on women with a family history of breast cancer. Published studies with prospective designs and randomized controlled trials were included in the review, and the psychological outcomes assessed were generalized psychological distress, generalized anxiety, depression, and breast cancer anxiety. Other outcomes investigated were the accuracy of perceived risk of developing breast cancer, breast cancer genetics knowledge and breast cancer screening uptake. A meta-analysis was performed to estimate effect size, where sufficient data were available. A total of 12 studies, most of which measured several outcomes, met at least one of the inclusion criteria. A sufficiently large number of studies were available to assess the magnitude of effects on three outcomes: generalized psychological distress, generalized anxiety and accuracy of perceived risk of developing breast cancer. The quantitative synthesis showed that genetic counselling leads to statistically significant decreases in generalized anxiety, with an average weighted effect sizes of r = - 0.17 (p<0.01). In contrast, the reduction in psychological distress exhibited a trend towards statistical significance only, with r = -0.074 (p = 0.052). The impact of genetic counselling on the accuracy of perceived risk was associated with an effect size of r = 0.56 (p<0.01). Thus in this meta-analysis, we demonstrated the efficacy of genetic counselling in meeting two of its objectives: reducing women's anxiety levels and improving the accuracy of their perceived risk. This review highlighted that most research so far focused on generalized distress and anxiety and accuracy of perceived risk, to the exclusion of other, perhaps equally important, types of outcomes. Future studies are likely to lead to more comprehensive assessments if additional emotional, cognitive and behavioural outcomes are included in the assessment.
UI - 11895911
AU - Assersohn L; Gangi L; Zhao Y; Dowsett M; Simon R; Powles TJ; Liu ET
TI - The feasibility of using fine needle aspiration from primary breast cancers for cDNA microarray analyses.
SO - Clin Cancer Res 2002 Mar;8(3):794-801
AD - Royal Marsden Hospital, Surrey SM2 5PT, United Kingdom.
PURPOSE: Our aims in this pilot study were to determine whether fine needle aspirates (FNAs) provide a sufficient quantity of mRNA for cDNA microarray analysis, produce a set of quality control criteria to accept individual arrays, and determine whether gene expression profiles obtained from FNAs were representative of the source tumor. EXPERIMENTAL DESIGN: Twenty-seven women with breast cancer for treatment with primary surgery had a FNA before and at the time of surgery, and a portion of excised tumor was taken for array analysis. Control experiments were performed using two Ewing's sarcoma xenograft models. mRNA was extracted from the samples and hybridized with the reference (MCF7 cell line) on cDNA microarrays. Statistical methods were applied to identify acceptability criteria for the arrays. RESULTS: Statistical analyses demonstrated that an adequate array could be identified by calculating the SD of the log of fluorescence intensities from the arrays. Using this criterion, only 4 of the 27 patients (15%) had FNA samples suitable for array analysis. Gene expression profiles from the FNAs closely resembled that of the corresponding source tumors and were clearly distinguished from FNAs derived from the xenografts. CONCLUSIONS: SD is a useful quality index for the clinical application of cDNA microarrays. This "proof of principle" study demonstrates that FNAs from primary breast cancers can be used for microarray analysis, although without amplification, it is feasible in only a small proportion of patients. For this to be clinically useful, validated amplification techniques for FNA samples are probably required.
UI - 12037674
AU - Claes K; Vandesompele J; Poppe B; Dahan K; Coene I; De Paepe A; Messiaen
TI - L Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1 exon 5 increase alternative transcript levels in the 5' end of the BRCA1 gene.
SO - Oncogene 2002 Jun 13;21(26):4171-5
AD - Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
We report two novel mutations in the splice sites of BRCA1 exon 5: IVS5+3A>G, a Belgian founder mutation, and IVS3-6T>G, identified in one family with a strong family history of breast cancer. Real-time RT-PCR showed that IVS3-6T>G leads to a fivefold increase of the BRCA1-Deltaex5 (isoform with an in frame skip of exon 5) ratio to the total BRCA1 expression level. IVS5+3A>G results in a 10-fold increase of the BRCA1-Delta22ntex5 ratio (isoform with an out of frame skip of the last 22 nucleotides of exon 5) and a twofold increase of the BRCA1-Deltaex5 ratio. These altered ratios are most likely to result from increased expression of the alternative transcripts, although we cannot completely rule out a small decrease of the total BRCA1 expression level due to highly variable BRCA1 levels in cultured cell lines. In order to explore the functional significance of the isoforms, we evaluated their prevalence in normal tissues and cancer cell lines. The BRCA1-Delta22ntex5 ratio was significantly higher in an ovarian cancer cell line compared to normal ovarian tissue. Our findings suggest that revealing the defects caused by some splice mutations requires accurate quantitative methods. We hypothesize that disruption of alternative transcript ratios of BRCA1 may be a dominant mechanism affecting predisposition to hereditary breast and/or ovarian cancer.
UI - 10699071
AU - Xie D; Shu XO; Deng Z; Wen WQ; Creek KE; Dai Q; Gao YT; Jin F; Zheng W
TI - Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk.
SO - J Natl Cancer Inst 2000 Mar 1;92(5):412-7
AD - Department of Epidemiology and Biostatistics, University of South Carolina School of Public Health and South Carolina Cancer Center, Columbia, SC 29203, USA.
BACKGROUND: Alterations of the HER2 (also known as erbB-2 or neu) proto-oncogene have been implicated in the carcinogenesis and prognosis of breast cancer. A polymorphism at codon 655 (GTC/valine to ATC /isoleucine [Val(655)Ile]) in the transmembrane domain-coding region of this gene has been identified and may be associated with the risk of breast cancer. We evaluated this hypothesis in a subgroup of women who participated in a large-scale, population-based, case-control study of breast cancer in Shanghai, China. METHODS: Genomic DNA from 339 patients with breast cancer and 361 healthy control subjects was examined for the Val(655)Ile polymorphism with a polymerase chain reaction-restriction fragment-length polymorphism-based assay. All study subjects completed a structured questionnaire during an in-person interview. All P values are from two-sided tests. RESULTS: We found that 25.1% of the case patients and 21.7% of the control subjects were heterozygous for the Val allele and 3.2% of the case patients and 0. 3% of the control subjects were homozygous for this allele (P =.005). Compared with women with the Ile/Ile genotype, women who had the Ile/Val or Val/Val genotype had an elevated risk of breast cancer (odds ratio [OR] = 1.4; 95% confidence interval [CI] = 1.0-2.0; P =. 05) after adjustment for age, educational level, study period, history of breast fibroadenoma, leisure physical activity, and age at first live birth. The risk was elevated even more among women who were homozygous for the Val allele (OR = 14.1; 95% CI = 1.8-113.4). The association was more pronounced among younger women (=45 years) than among older women (>45 years). The adjusted OR associated with the Val allele was 1.7 (95% CI = 1.1-2.6) for younger women and 1.0 (95% CI = 0.5-1.9) for older women. CONCLUSIONS: Results of this study suggest that polymorphisms of the HER2 gene may be important susceptibility biomarkers for breast cancer risk, particularly among younger women.
UI - 11829055
AU - Bredart A; Autier P; Riccardo A; Audisio A; Geraghty JG
TI - Psychosocial dimensions of BRCA testing: an overshadowed issue.
SO - Eur J Cancer Care (Engl) 2001 Jun;10(2):96-9
AD - Psycho-Oncology Research Unit, European Institute of Oncology, Milan, Italy.
Routine cancer susceptibility testing will soon be feasible in clinical practice. However, to date, this new technology has entailed many limitations, including potential adverse psychosocial consequences. Empirical studies examining these psychosocial aspects are strikingly scarce, especially in continental European countries. Are we prepared for managing the psychosocial problems that emerge from widespread introduction of this practice? Current research do not take into account cross-cultural variations in attitudes and reactions towards genetic testing. This paper points to the urgent need for obtaining a more accurate picture on the psychosocial aspects of breast cancer gene testing and disclosure in order to design recommendations for implementation in populations with highly variable cultural and legal background.
UI - 12021784
AU - Li J; Yang Y; Peng Y; Austin RJ; van Eyndhoven WG; Nguyen KC; Gabriele
TI - T; McCurrach ME; Marks JR; Hoey T; Lowe SW; Powers S Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23.
SO - Nat Genet 2002 Jun;31(2):133-4
AD - Tularik Inc., Genomics Division, 266 Pulaski Road, Greenlawn, New York, USA.
We found that PPM1D, encoding a serine/threonine protein phosphatase, lies within an epicenter of the region at 17q23 that is amplified in breast cancer. We show that overexpression of this gene confers two oncogenic phenotypes on cells in culture: attenuation of apoptosis induced by serum starvation and transformation of primary cells in cooperation with RAS.
UI - 12021785
AU - Bulavin DV; Demidov ON; Saito S; Kauraniemi P; Phillips C; Amundson SA;
TI - Ambrosino C; Sauter G; Nebreda AR; Anderson CW; Kallioniemi A; Fornace AJ Jr; Appella E Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity.
SO - Nat Genet 2002 Jun;31(2):210-5
AD - Gene Response Section, Bethesda, Maryland 20892, USA.
Expression of oncogenic Ras in primary human cells activates p53, thereby protecting cells from transformation. We show that in Ras-expressing IMR-90 cells, p53 is phosphorylated at Ser33 and Ser46 by the p38 mitogen-activated protein kinase (MAPK). Activity of p38 MAPK is regulated by the p53-inducible phosphatase PPM1D, creating a potential feedback loop. Expression of oncogenic Ras suppresses PPM1D mRNA induction, leaving p53 phosphorylated at Ser33 and Ser46 and in an active state. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest. Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice. The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53. These findings suggest that inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification contributes to the development of human cancers by suppressing p53 activation.
UI - 11786401
AU - Schubert EL; Hsu L; Cousens LA; Glogovac J; Self S; Reid BJ; Rabinovitch
TI - PS; Porter PL Single nucleotide polymorphism array analysis of flow-sorted epithelial cells from frozen versus fixed tissues for whole genome analysis of allelic loss in breast cancer.
SO - Am J Pathol 2002 Jan;160(1):73-9
AD - Division of Human Biology, Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Analysis of allelic loss in archival tumor specimens is constrained by quality and quantity of tissue and by technical limitations on the number of chromosomal sites that can be efficiently evaluated in conventional analyses using polymorphic microsatellite markers. Newly developed array-based assays have the potential to yield genome-wide data from small amounts of tissue but have not been validated for use with routinely processed specimens. We used the Affymetrix HuSNP assay, composed of 1494 single nucleotide polymorphism sites, to compare allelic loss results obtained from both formalin-fixed and frozen breast tissue samples. Tumor cells were separated from normal epithelia and nonepithelial cells by dissection and bivariate cytokeratin/DNA flow sorting; normal breast cells from the same patient served as constitutive normal. Allele results from the HuSNP array averaged 96% reproducibility between duplicates and were concordant between the fixed and frozen normal samples. We also analyzed DNA from the same samples after whole-genome amplification (primer extension preamplification). Although overall signal intensities were lower, the genotype data from the primer extension preamplification material was concordant with genomic DNA data from the same samples. Results from genomic normal tissue DNA averaged informative single nucleotide polymorphism at 379 (25%) loci genome-wide. Although data points were clustered and some segments of chromosomes were not informative, our data indicated that the Affymetrix HuSNP assay could provide an efficient and valid genome-wide analysis of allelic imbalance in routinely processed and whole genome-amplified pathology specimens.
UI - 10699056
AU - Brain K; Gray J; Norman P; Parsons E; Clarke A; Rogers C; Mansel R;
TI - Harper P Why do women attend familial breast cancer clinics?
SO - J Med Genet 2000 Mar;37(3):197-202
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
The increasing demand for genetic assessment for familial breast cancer has necessitated the development of cancer genetics services. However, little is known about the factors motivating the client population likely to approach these services. A cross sectional questionnaire survey of 1000 women with a family history of breast cancer was conducted to identify self-reported reasons for attending a familial breast cancer clinic and possible differences in the characteristics of women who were attending for diverse reasons. Before attendance at clinic, 833 women completed a baseline questionnaire (83% response rate). Women who gave personal risk (n=188), awareness of a family history (n=120), risk to family members (n=84), reassurance (n=69), genetic testing (n=65), breast screening (n=46), or prevention (n=39) as their main reason for attending were compared on demographic and medical variables, and on psychological variables including general anxiety, cancer worry, perceived risk, and attitudes towards prophylactic surgery and genetic testing. Important differences in the psychological characteristics of these groups were found, which were unrelated to reported family history. In particular, women who primarily wanted genetic testing felt extremely vulnerable to developing breast cancer, were more likely to be considering prophylactic surgery, and perceived fewer limitations of testing. Those who primarily wanted reassurance were highly anxious about the disease. We recommend that cancer genetics services take into consideration the informational and psychological needs and concerns of their client group.
UI - 12070248
AU - Foulkes WD; Brunet JS; Wong N; Goffin J; Chappuis PO
TI - Change in the penetrance of founder BRCA1/2 mutations? A retrospective cohort study.
SO - J Med Genet 2002 Jun;39(6):407-9
UI - 12064337
AU - Bernard-Gallon DJ; Vissac-Sabatier C; Antoine-Vincent D; Rio PG;
TI - Maurizis JC; Fustier P; Bignon YJ Differential effects of n-3 and n-6 polyunsaturated fatty acids on BRCA1 and BRCA2 gene expression in breast cell lines.
SO - Br J Nutr 2002 Apr;87(4):281-9
AD - Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, Clermont-Ferrand, France.
Current evidence strongly supports a role for the breast tumour suppressor genes, BRCA1 and BRCA2, in both normal development and carcinogenesis. In vitro observations reported that BRCA1 and BRCA2 are expressed in a cell cycle-dependent manner. Interestingly, differences in the actions of n-3 and n-6 polyunsaturated fatty acids have been observed: while the n-3 polyunsaturated fatty acids have been described to reduce pathological cell growth, the n-6 polyunsaturated fatty acids have been found to induce tumour proliferation. Here, we examined the expression of BRCA1 and BRCA2 in breast cell lines after treatment with polyunsaturated fatty acids. Real-time quantitative polymerase chain reaction determinations conclusively demonstrated increases in BRCA1 and BRCA2 mRNA expressions in MCF7 and MDA-MB 231 tumour cell lines after treatment with n-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid), but no variation was noticed with the n-6 polyunsaturated fatty acid (arachidonic acid). On the other hand, no variation of the expression of BRCA1 and BRCA2 mRNA was detected in MCF10a normal breast cell line treated by polyunsaturated fatty acids. The level of BRCA1 and BRCA2 proteins quantified by affinity chromatography remained unchanged in tumour (MCF7, MDA-MB 231) and normal (MCF10a) breast cell lines. We suggest the presence of a possible transcriptional or post-transcriptional regulation of BRCA1 and BRCA2 after n-3 polyunsaturated fatty acid treatment in breast tumour cells.
UI - 12019145
AU - Miksicek RJ; Myal Y; Watson PH; Walker C; Murphy LC; Leygue E
TI - Identification of a novel breast- and salivary gland-specific, mucin-like gene strongly expressed in normal and tumor human mammary epithelium.
SO - Cancer Res 2002 May 15;62(10):2736-40
AD - Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. email@example.com
Expression profiling using the public expressed sequence tag (EST) and serial analysis of gene expression (SAGE) databases resulted in the identification of a putative breast-specific mRNA that we have termed small breast epithelial mucin (SBEM). Hybridization analysis performed on 43 normal human tissues revealed that the SBEM gene was only expressed in mammary and salivary glands. Further reverse-transcription PCR analyses confirmed SBEM expression in most of established human breast epithelial cell lines analyzed (7 of 8) but not in cell lines of non-breast origin (0 of 6). SBEM mRNA expression was detected in >90% of invasive ductal carcinomas and correlated with the expression of a previously characterized breast-specific gene, mammaglobin-1 (n = 54; Spearman r = 0.34, P = 0.011). Interestingly, a higher SBEM:mammaglobin-1 ratio was observed in primary tumors with axillary lymph node metastasis than in node-negative tumors (n = 46; Mann-Whitney, P = 0.04). In a subset of 20 primary breast tumors and their matched axillary lymph nodes, a high concordance (Fisher's exact test, P < 0.001) was seen between PCR detection of SBEM mRNA in lymph node tissue and their histopathological status, indicating that SBEM mRNA expression is conserved in nodal metastasis. The SBEM gene is predicted to code for a putative low molecular weight, secreted sialoglycoprotein, potentially useful for the diagnosis of metastatic breast cancer.
UI - 12019146
AU - Bell DW; Erban J; Sgroi DC; Haber DA
TI - Selective loss of heterozygosity in multiple breast cancers from a carrier of mutations in both BRCA1 and BRCA2.
SO - Cancer Res 2002 May 15;62(10):2741-3
AD - Center for Cancer Risk Analysis, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Carriers of one mutant allele of either BRCA1 or BRCA2 are at risk for somatic loss of the second wild-type allele, leading to the initiation of breast tumorigenesis. We identified a patient of Ashkenazi Jewish heritage with germ-line heterozygous mutations in both BRCA1 (5382insC) and BRCA2 (6174delT), who had developed three independent breast cancers by age 47. Two breast cancers demonstrated inactivation of both BRCA2 alleles but retention of the wild-type BRCA1 allele, and the third showed loss of heterozygosity for BRCA1 but not BRCA2. The observation that breast tumors arising in a double heterozygote show biallelic inactivation of either BRCA1 or BRCA2, but not both, suggests that these genetic events are functionally equivalent in initiating tumorigenesis. The distinct histopathological features of these tumors may reflect the acquisition of subsequent genetic events.
UI - 12019156
AU - Hewitt SC; Bocchinfuso WP; Zhai J; Harrell C; Koonce L; Clark J; Myers
TI - P; Korach KS Lack of ductal development in the absence of functional estrogen receptor alpha delays mammary tumor formation induced by transgenic expression of ErbB2/neu.
SO - Cancer Res 2002 May 15;62(10):2798-805
AD - Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC 27709, USA.
Expression of the mouse mammary tumor virus (MMTV) neu/erbB2 transgene in mice induces mammary tumors. To examine the effect of removing estrogen receptor alpha (ERalpha) signaling on the ability of an MMTV-neu/erbB2 transgene to induce mammary tumors, the neu transgene was expressed in the ERalpha knockout (alphaERKO) mouse, which lacks functional ERalpha. MMTV-neu females that lacked ERalpha still developed mammary tumors; however, tumor onset was significantly delayed. This study indicates that ERalpha is not required for mammary tumor induction by overexpression of neu/erbB2, but plays a role in the rate of tumor onset. The removal of ovarian steroid by ovariectomy in adults did not alter the onset rate. In contrast, prepubertal ovariectomy, which arrested mammary epithelial development, significantly delayed onset. In addition, manipulations that increase progesterone also accelerate the tumor onset, indicating the slower onset in the alphaERKO is primarily attributable to the anovulatory phenotype resulting in lack of progesterone stimulation and a decreased abundance of target cells in the alphaERKO mammary gland.
UI - 11965197
AU - Friedenson B
TI - A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision.
SO - MedGenMed 2001 Nov 2;3(6):2
AD - Department of Biochemistry and Molecular Biology at the University of Illinois at Chicago, Chicago, Illinois, USA. molmeddoc@Yahoo.com.
A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.
UI - 11982338
AU - Kim H; Pirrung MC
TI - Arrayed primer extension computing with variant mRNA splice forms. Multiple isoforms of CD44 in a human breast tumor.
SO - J Am Chem Soc 2002 May 8;124(18):4934-5
AD - Department of Chemistry, Levine Science Research Center, Duke University, Durham, North Carolina 27708-0317, USA.
UI - 11991720
AU - Nielsen HL; Ronnov-Jessen L; Villadsen R; Petersen OW
TI - Identification of EPSTI1, a novel gene induced by epithelial-stromal interaction in human breast cancer.
SO - Genomics 2002 May;79(5):703-10
AD - Structural Cell Biology Unit, Department of Medical Anatomy A, the Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
During growth, invasion, and metastasis, tumor cells interact extensively with the surrounding stroma. To identify genes that are upregulated during this process, we compared mRNA pooled from tumor cells and fibroblasts cultured separately to mRNA from cells in coculture. Using differential display (DD), a transcript representing a novel gene, designated epithelial-stromal interaction 1 (breast) (EPSTI1), was identified. EPSTI1 showed no homology to any known gene, but matched a cluster of expressed-sequence tags (ESTs). The full-length cDNA of 1508 bp was generated by 5'-RACE, included an open reading frame (ORF) encoding a putative 307-amino-acid protein, and mapped to chromosome 13q13.3. EPSTI1 was highly upregulated in invasive breast carcinomas compared with normal breast. In a tissue mRNA panel the most prominent expression of EPSTI1 was found in placenta. Thus, EPSTI1 is a novel human gene expressed in tissues characterized by extensive epithelial-stromal interaction, and expression of this gene may be a crucial event in invasion and metastasis of cancer.
UI - 12027444
AU - Fuchs M; Hutzler P; Brunner I; Schlegel J; Mages J; Reuning U; Hapke S;
TI - Duyster J; Hirohashi S; Genda T; Sakamoto M; Uberall F; Hofler H; Becker KF; Luber B Motility enhancement by tumor-derived mutant E-cadherin is sensitive to treatment with epidermal growth factor receptor and phosphatidylinositol 3-kinase inhibitors.
SO - Exp Cell Res 2002 Jun 10;276(2):129-41
AD - Klinikum rechts der Isar, Institut fur Allgemeine Pathologie und Pathologische Anatomie, Technische Universitat Munchen, Munich, Germany.
Diffuse-type gastric and lobular breast cancers are characterized by frequent mutations in the cell adhesion molecule E-cadherin. Here we report that tumor-associated mutations of E-cadherin enhanced random cell movement of transfected MDA-MB-435S mammary carcinoma cells as compared to wild-type (wt) E-cadherin-expressing cells. The mutations included in frame deletions of exons 8 or 9 and a point mutation in exon 8 which all affect putative calcium-binding sites within the linker region of the second and third extracellular domain. Motility enhancement by mutant E-cadherin was investigated by time-lapse laser scanning microscopy. Increased cell motility stimulated by mutant E-cadherin was influenced by cell-matrix interactions. The motility-increasing activity of mutant E-cadherin was blocked by application of pharmacological inhibitors of epidermal growth factor receptor and phosphatidylinositol (PI) 3-kinase. Investigation of the activation status of PI 3-kinase and the downstream signaling molecules Akt/protein kinase B and MAP kinase p44/42 showed that these kinases are not more strongly activated in mutant E-cadherin-expressing cells than in wt E-cadherin-expressing cells. Instead, the basal level of PI 3-kinase is necessary for mutant E-cadherin-enhanced cell motility. Our data suggest a critical role of E-cadherin mutations for the fine tuning of tumor cell motility. (c) 2002 Elsevier Science (USA).
UI - 12027462
AU - Dong Y; Asch HL; Ying A; Asch BB
TI - Molecular mechanism of transcriptional repression of gelsolin in human breast cancer cells.
SO - Exp Cell Res 2002 Jun 10;276(2):328-36
AD - Division of Experimental Pathology, Roswell Park Cancer Institute (RPCI), Buffalo, New York 14263, USA.
Loss of gelsolin, a tumor suppressor, is one of the most frequently occurring molecular defects in breast cancers of diverse etiologies and across at least three animal species: human, mouse, and rat. Our previous analysis of breast cancer cells demonstrated that the deficiency is not due to mutation of the gelsolin gene, but instead to epigenetic factors, including decreased transcription of the gene. The study described herein provides the first functional characterization of the human gelsolin promoter and reveals a mechanistic basis for the reduced gelsolin transcription. In reporter gene assays, the gelsolin promoter was less active in low-gelsolin-expressing breast cancer cells. A cis-element mediating this reduced promoter activity was defined as a 27-bp sequence located approximately 135 bp upstream of the transcription start site. Gel shift and supershift assays and Southwestern blotting analysis indicated that activating transcription factor-1 (ATF-1) and a protein of approximately 100 kDa may have cancer cell-specific DNA-binding activity to the 27-bp gelsolin cis-element. Although the ATF-1 protein was highly expressed in both benign and tumorigenic breast cells, its DNA-binding activity was selectively abundant in the cancer cells and correlated inversely with the gelsolin mRNA level. Thus, our results suggest a role for ATF-1 in gelsolin promoter silencing in contrast to its transactivating effect on various other promoters. (c) 2002 Elsevier Science (USA).
UI - 12055674
AU - Bose S; Crane A; Hibshoosh H; Mansukhani M; Sandweis L; Parsons R
TI - Reduced expression of PTEN correlates with breast cancer progression.
SO - Hum Pathol 2002 Apr;33(4):405-9
AD - Department of Pathology, University of California, Los Angeles, California 90048, USA.
PTEN is a tumor-suppressor gene with phosphatase activity that is mutated in a variety of cancers. We analyzed a series of 34 invasive and 18 in situ breast cancers with known molecular status of the PTEN genotype using immunohistochemistry. Reduced PTEN protein expression was seen in 38% of invasive cancers and in 11% of in situ cancers. The frequency of reduced expression was highest in stage II and III cancers. Reduced expression also correlated with aneuploidy. In addition, in tumors with both in situ and invasive components, expression within the ductal carcinoma in situ portion tended to reflect the expression pattern of the invasive component. These data suggest that PTEN expression is frequently reduced in advanced breast cancers. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 11891178
AU - Zysman MA; Chapman WB; Bapat B
TI - Considerations when analyzing the methylation status of PTEN tumor suppressor gene.
SO - Am J Pathol 2002 Mar;160(3):795-800
AD - Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Epigenetic mechanisms of gene silencing, including promoter hypermethylation of tumor suppressor genes, have been shown to contribute to tumorigenesis. PTEN is an important tumor suppressor implicated in the pathogenesis of a number of familial and sporadic cancers. Germline mutations of PTEN predispose to dominantly inherited hamartomatous disorders Cowden syndrome and Bannayan-Zonana syndrome. Somatic PTEN mutations commonly occur in endometrial, breast, prostate, and thyroid tumors. Several investigators have speculated on PTEN promoter hypermethylation as a possible mechanism of PTEN inactivation but data supporting such observations is not forthcoming. The genomic sequence of PTEN is 98% identical to a highly conserved processed PTEN pseudogene (psiPTEN) and this sequence identity extends 841 base pairs into the promoter region. This high degree of homology has made analysis of the methylation status of the PTEN promoter quite challenging. We have investigated the methylation profiles of the promoter region of PTEN in endometrial, breast, and colon cancer cell lines, as well as in a panel of primary endometrial tumors using a combination of methylation-specific polymerase chain reaction, methylation-sensitive restriction analysis, and bisulfite sequencing. Our results show that the pseudogene, and not PTEN, is predominantly methylated in cell lines and tumors. Without careful consideration of the critical nucleotide differences between the two sequences, results obtained from PTEN analysis may not necessarily represent the methylation status of PTEN.
UI - 11955796
AU - Druckmann R; Rohr UD
TI - IGF-1 in gynaecology and obstetrics: update 2002.
SO - Maturitas 2002 Apr 15;41 Suppl 1():S65-83
AD - Anemo-Menopause-Center, 12 Rue de France, F-06000, Nice, France. firstname.lastname@example.org
Recent discoveries on endocrine, paracrine and autocrine involvement of insulin-like growth factor-1 (IGF-1) in the proliferation of many tissues raised the attention of its role in reproduction and in the growth of various cancers as well as of benign proliferations. The intention of this article is to focus on IGF-1 in the field of gynaecology. Perimenopausal women who exhibit high IGF-1 and low IGF binding protein (IGFBP) levels, like IGFBG-3, have an increased risk of developing breast cancer. A higher risk for cervical, ovarian and endometrial cancer is related to high IGF-1 levels in post- and premenopausal women. It has been shown that myomas, by far the most common benign uterine tumor in women, grow in the presence of IGF-1, in vitro as well as in vivo. Studies show that IGF-1 is involved in the differentiation of various reproductive tissues, like endometrium and ovarian tissues. Patients suffering from polycystic ovary syndrome (PCO) frequently show insulin resistance accompanied by an increase of IGF-1 in plasma. Plasma IGF-1 levels are higher in cases of severe endometriosis, however, in endometriosis and in PCO IGF levels locally in the endometrium are reduced, what might explain infertility. Recently, it was shown that IGF facilitates the implantation of the human embryo in the endometrium during IVF. Implantation is a paradox where different immune systems have to collaborate to make implantation and survival of the pregnancy possible. IGF seems to be the starter molecule so that the two epithelia can fuse. A disturbance can result in complications during pregnancy i.e. spontaneous miscarriage, preeclampsia as well as defects of the embryo. Therefore, IGF is a useful marker in successful pregnancy as well. A better mechanistic understanding of IGF-1 action on the cellular lev