National Cancer Institute®
Last Modified: September 1, 2002
UI - 11822727
AU - Boucher KM; Kerber RA
TI - Measures of familial aggregation as predictors of breast-cancer risk.
SO - J Epidemiol Biostat 2001;6(5):377-85
AD - Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City 84112, USA.
BACKGROUND: Several measures of familial disease aggregation have been proposed, but only a few of these are designed to be implemented at the individual level. We evaluate two of them in the context of breast-cancer incidence. METHODS: A population-based cohort consisting of 114 429 women born between 1874 and 1931 and at risk for breast cancer after 1965 was identified by linking the Utah Population Data Base and the Utah Cancer Registry. Two competing methods were used to obtain predictors of familial aggregation of risk: the number of first-degree relatives with breast cancer (NIST) and the familial standardised incidence ratio (FSIR), which weights the disease status of relatives based on their degree of relatedness with the proband. Relative risks were estimated using Mantel-Haenszel. Poisson regression and spline regression methods. The age-dependent hazard function was also estimated. RESULTS: Compared to a baseline category containing 91.5% of the subjects, the 0.7% of subjects identified as high risk using the FSIR criterion had a relative risk of about 2.8, while those identified as high risk using the NIST criterion had a relative risk of 2.0. Moderate-risk subjects had a relative risk of about 1.75 using either criterion. FSIR was a significant predictor of risk even for those with no affected first-degree relatives. No decline in the baseline risk was observed at advanced ages. CONCLUSIONS: FSIR appears to be a better predictor of breast-cancer risk than NIST, particularly for high-risk subjects.
UI - 11927843
AU - Wang-Gohrke S; Becher H; Kreienberg R; Runnebaum IB; Chang-Claude J
TI - Intron 3 16 bp duplication polymorphism of p53 is associated with an increased risk for breast cancer by the age of 50 years.
SO - Pharmacogenetics 2002 Apr;12(3):269-72
AD - Department of Obstetrics and Gynaecology, Molecular Biology Laboratory, University of Ulm, Germany.
We used a large population-based case-control study to determine whether three known p53 polymorphisms, intron 3 16 bp duplication, codon 72(Arg/Pro) and intron 6 MspI restriction fragment length polymorphism, alter the risk for breast cancer in German women. For all three polymorphisms, the odds ratios (ORs) for breast cancer were increased in women carrying the rare allele; however, this was statistically significant only for the 16 bp duplication polymorphism. Compared with the 16 bp duplication wild-type A1/A1 genotype, ORs for A1/A2 genotype and A2/A2 genotype were 1.3 [95% confidence interval (CI) 1.0-1.7] and 1.7 (95% CI 0.8-3.4), suggesting an allele dosage effect (trend test, P = 0.03). Significant evidence was found for a differential effect by family history of breast cancer (P = 0.03 for interaction), with the OR being 5.3 among women with a first degree family history. Our data suggest that inheritance of an intronic polymorphism in the p53 gene increases breast cancer risk appreciably in women by the age of 50 years with a family history of breast cancer in the German population.
UI - 12161606
AU - Chappuis PO; Goffin J; Wong N; Perret C; Ghadirian P; Tonin PN; Foulkes
TI - WD A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer.
SO - J Med Genet 2002 Aug;39(8):608-10
UI - 12161607
AU - Kauff ND; Perez-Segura P; Robson ME; Scheuer L; Siegel B; Schluger A;
TI - Rapaport B; Frank TS; Nafa K; Ellis NA; Parmigiani G; Offit K Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families.
SO - J Med Genet 2002 Aug;39(8):611-4
UI - 12161611
AU - Caldes T; de la Hoya M; Tosar A; Sulleiro S; Godino J; Ibanez D; Martin
TI - M; Perez-Segura P; Diaz-Rubio E A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes.
SO - J Med Genet 2002 Aug;39(8):e44
UI - 11883440
AU - Masri MA; Abdel Seed NM; Fahal AH; Romano M; Baralle F; El Hassam AM;
TI - Ibrahim ME Minor role for BRCA2 (exon11) and p53 (exon 5-9) among Sudanese breast cancer patients.
SO - Breast Cancer Res Treat 2002 Jan;71(2):145-7
AD - Institute of Endemic Diseases, University of Khartoum, Sudan.
A cohort of 20 breast cancer patients from the Sudan was tested for germ line and somatic mutation in their BRCA2 exon 11 as well as the main conserved area of the p53 tumor suppressor gene. The results indicate that both regions may play a limited role in the pathogenesis of breast cancer in those patients. The fact that there are no somatic mutations detected in p53 was particularly surprising as the expected rate for mutations in breast cancer is 30-50%.
UI - 11890312
AU - Satagopan JM; Verbel DA; Venkatraman ES; Offit KE; Begg CB
TI - Two-stage designs for gene-disease association studies.
SO - Biometrics 2002 Mar;58(1):163-70
AD - Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. email@example.com
The goal of this article is to describe a two-stage design that maximizes the power to detect gene-disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near-optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.
UI - 12011455
AU - Desai KV; Xiao N; Wang W; Gangi L; Greene J; Powell JI; Dickson R; Furth
TI - P; Hunter K; Kucherlapati R; Simon R; Liu ET; Green JE Initiating oncogenic event determines gene-expression patterns of human breast cancer models.
SO - Proc Natl Acad Sci U S A 2002 May 14;99(10):6967-72
AD - Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
Molecular expression profiling of tumors initiated by transgenic overexpression of c-myc, c-neu, c-ha-ras, polyoma middle T antigen (PyMT) or simian virus 40 T/t antigen (T-ag) targeted to the mouse mammary gland have identified both common and oncogene-specific events associated with tumor formation and progression. The tumors shared great similarities in their gene-expression profiles as compared with the normal mammary gland with an induction of cell-cycle regulators, metabolic regulators, zinc finger proteins, and protein tyrosine phosphatases, along with the suppression of some protein tyrosine kinases. Selection and hierarchical clustering of the most variant genes, however, resulted in separating the mouse models into three groups with distinct oncogene-specific patterns of gene expression. Such an identification of targets specified by particular oncogenes may facilitate development of lesion-specific therapeutics and preclinical testing. Moreover, similarities in gene expression between human breast cancers and the mouse models have been identified, thus providing an important component for the validation of transgenic mammary cancer models.
UI - 12125210
AU - Jara L; Ampuero S; Seccia L; Bustamante M; Blanco R; Ojeda JM
TI - Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer.
SO - Biol Res 2002;35(1):85-93
AD - Human Genetics Program, Institute of Biomedical Sciences, School of Medicine, University of Chile. firstname.lastname@example.org
Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.
UI - 12114489
AU - MacDonald DJ; Choi J; Ferrell B; Sand S; McCaffrey S; Blazer KR; Grant
TI - M; Weitzel JN Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment.
SO - J Med Genet 2002 Jul;39(7):526-30
UI - 12114490
AU - McAllister M; O'Malley K; Hopwood P; Kerr B; Howell A; Evans DG
TI - Management of women with a family history of breast cancer in the North West Region of England: training for implementing a vision of the future.
SO - J Med Genet 2002 Jul;39(7):531-5
UI - 12114492
AU - Kwiatkowska E; Brozek I; Izycka-Swieszewska E; Limon J; Mackiewicz A
TI - Novel BRCA2 mutation in a Polish family with hamartoma and two male breast cancers.
SO - J Med Genet 2002 Jul;39(7):E35
UI - 12151349
AU - Forsti A; Jin Q; Grzybowska E; Soderberg M; Zientek H; Sieminska M;
TI - Rogozinska-Szczepka J; Chmielik E; Utracka-Hutka B; Hemminki K Sex hormone-binding globulin polymorphisms in familial and sporadic breast cancer.
SO - Carcinogenesis 2002 Aug;23(8):1315-20
AD - Department of Biosciences at Novum, Karolinska Institute, SE-14157 Huddinge, Sweden. email@example.com
Ovarian steroids are one of the strongest risk factors for breast cancer. Sex hormone-binding globulin (SHBG) binds and transports sex steroids in the blood, regulating their bioavailable fraction and access to target cells. It can also inhibit the estradiol-induced proliferation of breast cancer cells through its membrane receptor. Three coding-region polymorphisms, which lead to an amino acid change, have been reported. We studied the influence of these three polymorphisms on breast cancer risk in three different populations: Polish familial breast cancer cases, 27% of them carrying a BRCA1/BRCA2 mutation, Nordic familial and sporadic breast cancer cases. The reported G to A polymorphism in exon 1 was not found in the 423 analyzed samples. Instead, we found a C to T transition causing an arg to cys amino acid change within the same codon in one Polish breast cancer patient and her daughter. Both of them were heterozygotes for the exon 8 G to A polymorphism as well. They were diagnosed for bilateral breast cancer and carried a BRCA1 mutation (5382insC). Analysis of the tumor samples showed that they had lost the wild-type allele both at exons 1 and 8 of the SHBG gene. Analysis of the other Polish samples showed no correlation of the exon 8 polymorphism to breast cancer, bilateral breast cancer, BRCA1/BRCA2 mutations or age at diagnosis. No association of the exon 8 polymorphism with breast cancer in the Nordic familial or sporadic cases was found. The C to T polymorphism located in exon 4 was rare in all the studied populations (overall allele frequency 0.011). However, in each of the study populations there was a trend for a lower variant allele frequency in cancer cases than in controls. Variant allele frequency in all the breast cancer cases was significantly lower than in all the controls (chi(2) = 5.27, P-value 0.02; odds ratio = 0.23, 95% confidence interval 0.05-0.84).
UI - 12174988
AU - Meguerditchian AN; Falardeau M; Martin G
TI - Male breast carcinoma.
SO - Can J Surg 2002 Aug;45(4):296-302
AD - Department of Surgery, Universite Laval, Quebec City, Que.
OBJECTIVE: To review the epidemiology, presentation, diagnosis, molecular genetics, treatment and prognosis of male breast cancer. DATA SOURCES: Articles, written in English or French, selected from the "male breast cancer," according to the following criteria: covering institutional experience or comparing diagnostic and treatment modalities, and epidemiologic or general reviews. STUDY SELECTION: Of 198 articles found 50 fulfilled the review criteria. DATA SYNTHESIS: Risk factors included advanced age, a positive family history, Jewish origin, black race, excess exposure to female hormones (Klinefelter's syndrome), environmental exposure (irradiation), alcohol, obesity, higher socioeconomic or higher educational status and childlessness. Gynecomastia remains a controversial factor, this term being used for both a histologic reality and a physical finding. Advanced disease is characterized by pain, bloody discharge and skin ulceration. There is no definitive diagnostic algorithm. Experience with male breast mammography is limited, and imaging is less informative for patients under 50 years of age. Fine-needle aspiration tends to overestimate the rate of malignancy. The commonest histologic finding is infiltrating ductal adenocarcinoma. Treatment includes modified radical mastectomy, followed by cyclophosphamide-methotrexate-5-fluorouracil or 5-fluorouracil-Adriamycin-cyclophosphamide chemotherapy for disease of stage II or greater. Radiotherapy does not seem to add any benefit. The disease is highly receptor-positive; however, many patients discontinue tamoxifen due to side effects. The most important prognostic factors are tumour size, lymphatic invasion and axillary node status. CONCLUSIONS: Because of the low incidence of male breast cancer, advances will be obtained mainly with the rapid transfer of newly gained knowledge in female mammary neoplasia. The increased use of adjuvant chemotherapy combined with tamoxifen postoperatively may have a positive impact on survival. Public education should be oriented toward men at higher risk to reduce the interval between appearance of symptoms and consultation. Rigorous data collection will allow for thorough reporting of risk factors and thus the possibility of characterizing the etiology of this disease.
UI - 11767003
AU - Yang Q; Yoshimura G; Nakamura M; Nakamura Y; Shan L; Suzuma T; Tamaki T;
TI - Umemura T; Mori I; Kakudo K Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor beta2 expression in breast carcinoma.
SO - Breast Cancer Res Treat 2001 Nov;70(1):39-45
AD - Department of Surgery, Kihoku Hospital, Wakayama Medical University School of Medicine, Wakayama City, Japan. firstname.lastname@example.org
A tumor suppressor gene. retinoic acid receptor (RAR) beta2, has been mapped to chromosome 3p24, a region where loss of heterozygosity (LOH) has been observed commonly in carcinomas of various tumor tissues. RAR beta2 expression is reduced or lost in many malignant tumors including breast cancer, however, whether LOH accounts for the loss of expression of RAR beta2 in breast cancer is unknown. We, therefore, assessed LOH on chromosome band 3p24 to correlate it with RAR beta2 expression and other established prognostic parameters in 52 breast carcinomas. Based on three microsatellites, D3S 1283, D3S 1293 and D3S 1286. all of the tumors were informative, of these, 12 (23%) exhibited LOH. RAR beta2 expression was lost in 42% (19/45) of these samples. We found that LOH on chromosome band 3p24 was not correlated with loss of RAR beta2, but correlated with higher histological grade, p53-positivity, and loss of estrogen and progesterone receptors. Our findings suggest that LOH of the RAR beta2 gene does not account for the frequent loss of RAR beta2 expression in breast cancer but the genomic structural alteration at or close to the RAR beta2 gene locus are likely to be associated with tumor progression and/or loss of hormonal dependency.
UI - 12096126
AU - Gharbi S; Gaffney P; Yang A; Zvelebil MJ; Cramer R; Waterfield MD; Timms
TI - JF Evaluation of two-dimensional differential gel electrophoresis for proteomic expression analysis of a model breast cancer cell system.
SO - Mol Cell Proteomics 2002 Feb;1(2):91-8
AD - Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, United Kingdom.
The technique of fluorescent two-dimensional (2D) difference gel electrophoresis for differential protein expression analysis has been evaluated using a model breast cancer cell system of ErbB-2 overexpression. Labeling of paired cell lysate samples with N-hydroxy succinimidyl ester-derivatives of fluorescent Cy3 and Cy5 dyes for separation on the same 2D gel enabled quantitative, sensitive, and reproducible differential expression analysis of the cell lines. SyproRuby staining was shown to be a highly sensitive and 2D difference gel electrophoresis-compatible method for post-electrophoretic visualization of proteins, which could then be picked and identified by matrix-assisted laser-desorption ionization mass spectroscopy. Indeed, from these experiments, we have identified multiple proteins that are likely to be involved in ErbB-2-mediated transformation. A triple dye labeling methodology was used to identify proteins differentially expressed in the cell system over a time course of growth factor stimulation. A Cy2-labeled pool of samples was used as a standard with all Cy3- and Cy5-labeled sample pairs to facilitate cross-gel quantitative analysis. DeCyder (Amersham Biosciences, Inc.) software was used to distinguish clear statistical differences in protein expression over time and between the cell lines.
UI - 12101106
AU - Li CI; Malone KE; Daling JR
TI - Differences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jul;11(7):601-7
AD - Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington 98109-1024, USA. email@example.com
Numerous studies have demonstrated differences in certain biological breast cancer characteristics associated with survival, including hormone receptor status and histology, among women of different racial and ethnic groups. However, women classified as "Asian or Pacific Islanders" or "Hispanic whites" represent heterogeneous populations, and few studies have separately evaluated subgroups of these populations with respect to these breast tumor characteristics. Using data obtained from 11 cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program, the tumor characteristics of 93,317 women in whom invasive breast cancer was diagnosed from 1992 to 1998 were compared by race and ethnicity using unconditional and polytomous logistic regression. The study consisted of 75,978 non-Hispanic whites, 6,915 African Americans, 203 Native Americans, 5,750 Asians/Pacific Islanders, and 4,471 Hispanic whites. Eight Asian/Pacific Islander and four Hispanic white subgroups were also analyzed separately. Relative to non-Hispanic whites, African Americans, Native Americans, Filipinos, Chinese, Koreans, Vietnamese, Indians/Pakistanis, Mexicans, South/Central Americans, and Puerto Ricans living in the United States had 1.4- to 3.1-fold elevated risks of presenting with estrogen receptor-negative/progesterone receptor-negative breast cancer. Numerous differences by histological type, including lobular, ductal/lobular, mucinous, comedocarcinoma, tubular, and medullary histologies, were also observed by race/ethnicity. Breast cancer tumor characteristics differ by race/ethnicity in the United States. Both biological and lifestyle factors likely contribute to these findings. Our results may explain, to some extent, the differences in breast cancer stage and survival observed by race/ethnicity. Understanding the factors underlying these differences may provide further insight into breast cancer etiology in different populations.
UI - 12135856
AU - Bertucci F; Nasser V; Houlgatte R; Birnbaum D
TI - [Gene expression profiling using cDNA arrays and prognosis of breast cancer]
SO - Bull Cancer 2002 Jun;89(6):571-4
AD - Departement d'oncologie moleculaire (TAGC: technologies avancees pour le genome et la clinique), Institut Paoli-Calmettes, IFR57, 27, bd Le -Roure, 13009 Marseille, France.
Breast cancer is a major health problem. Clinical heterogeneity makes prognosis and sensitivity to treatment highly variable among patients. The recently developed cDNA array technology allows to analyse the expression of thousands of genes simultaneously. Results of the pioneering studies are promising: expression profiling of breast tumours using cDNA arrays seems able to identify new prognostic sub-classes unidentifiable using conventional parameters.
UI - 8083195
AU - Toh Y; Pencil SD; Nicolson GL
TI - A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses.
SO - J Biol Chem 1994 Sep 16;269(37):22958-63
AD - Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
To understand the genes involved in breast cancer invasion and metastasis, we analyzed a novel candidate metastasis-associated gene, mta1, which was isolated by differential cDNA library screening using the 13762NF rat mammary adenocarcinoma metastatic system. Northern blot analyses showed that the mRNA expression level of the mta1 gene was 4-fold higher in the highly metastatic cell line MTLn3 than in the nonmetastatic cell line MTC.4. The mta1 gene was expressed in various normal rat organs, especially in the testis, suggesting its essential normal function. The mRNA expression levels of the human homologue of this gene also correlated with the metastatic potential in two human breast cancer metastatic systems. The full-length mta1 cDNA sequence contained an open reading frame encoding a protein of 703 amino acid residues, and sequence analysis by data base homology search indicated that mta1 is a novel gene. The Mta1 protein contained several possible phosphorylation sites, and a proline-rich amino acid stretch at the carboxyl-terminal end completely matched the consensus sequence for the src homology 3 domain-binding motif. Using antibodies raised against glutathione S-transferase-Mta1 fusion protein or a synthetic oligopeptide, Western blots showed that the molecular mass of the Mta1 protein was approximately 80 kDa, and the levels of the Mta1 protein also correlated with the metastatic potential, results similar to those obtained from the Northern analyses. Thus, the novel gene mta1 may encode a molecule that is functional in normal cells as well as in breast cancer invasion and metastasis.
UI - 7607577
AU - Toh Y; Pencil SD; Nicolson GL
TI - Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines.
SO - Gene 1995 Jun 14;159(1):97-104
AD - Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
To understand the genes and gene products involved in breast cancer invasion and metastasis, we previously isolated ten differentially expressed genes by differential cDNA library screening techniques, using the 13762NF rat mammary adenocarcinoma metastatic system. In this study, we further analysed a novel candidate metastasis-associated gene, mta1, previously designated clone 10.14. Northern blotting analyses showed that the steady-state mRNA expression level of mta1 was fourfold higher in a highly metastatic line (MTLn3) than in a nonmetastatic line (MTC.4). The mta1 gene was expressed at low levels in various normal rat organs, except testis, where it was expressed in high amounts. The mRNA expression levels of the human homologue of this gene were also examined in two human breast cancer metastatic systems; the ratios of mRNA were estimated to be MCF-7 (nonmetastatic):MCF7/LCC1 (invasive):MCF7/LCC2 (metastatic) = 1:2:4 and MDA-MB-468 (nonmetastatic):MDA231 (metastatic) = 1:4. Thus, the expression of this gene directly correlated with metastatic potential in two human systems, as well as in the rat metastatic system. Clone 10.14 was used to isolate a full-length cDNA clone for mta1, yielding the clone p10.14-C4.5, which was sequenced and analysed. Clone p10.14-C4.5 was 2756-bp long and contained a single open reading frame that could encode a protein of 703 amino acid (aa) residues. The aa sequence of mta1 was found to be novel by database homology search and contained possible phosphorylation sites for tyrosine kinase, protein kinase C and casein kinase II. A Pro-rich stretch was found at the C-terminal end that completely matched the consensus sequence for the SH3-binding motif.(ABSTRACT TRUNCATED AT 250 WORDS)
UI - 9513727
AU - Nicolson GL
TI - Breast cancer metastasis-associated genes: role in tumour progression to the metastatic state.
SO - Biochem Soc Symp 1998;63():231-43
AD - Institute for Molecular Medicine, Irvine, CA 92614, USA.
Breast cancer patients usually do not die of their primary cancers; they die of metastatic disease. Thus understanding the progression of breast cancer to the metastatic state and the changes that take place in highly malignant breast cells are important goals that could eventually result in new therapeutic approaches to highly progressive breast disease. Changes in the expression of certain genes or alterations in gene structures and encoded products can result in benign tumour cells progressing to the metastatic state. Experimentally, this has been performed by transferring dominantly acting oncogenes into susceptible cells and then testing the malignant properties of these cells in suitable animal models, but such rapid qualitative changes occur in vivo only rarely, and the natural progression of mammary cells to the metastatic state is thought to occur through a slow stepwise process that can take several years. Some of the slow stepwise changes in mammary cancer progression can be reversible and need not involve dominantly acting oncogenes or tumour suppressor genes, consistent with clinical observations. An important element of the natural progression of mammary tumours to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity, a process that appears to involve mainly quantitative changes in gene expression, resulting in loss of normal cellular regulation. One of the important mechanisms of cellular regulation in epithelial tissues, such as those found in the breast, is mediated by intercellular junctional communication. Alterations in gene expression can result in loss of gap-junctional communication, concomitant with cellular diversification and progression. It is thought that the highly malignant cancer cells that have slowly evolved in vivo with only a few qualitative changes in gene structure have undergone extensive cycles of diversification and the accumulation of several quantitative changes in the expression of various genes that encode products related to malignancy. We have identified some of the genes that are related to progression and metastasis in breast cancer. For example, one of these genes, a novel gene called mta1 (in rodents) or MTA1 (in humans) appears to be involved in mammary cell motility and growth regulation. Thus highly malignant cellular phenotypes can arise rapidly due to specific qualitative changes in critical controlling genes, or more slowly via less critical qualitative genetic changes coupled with other cellular changes, such as loss of intercellular communication, and changes in gene expression, such as in the MTA1 gene, resulting in cellular diversification and ultimately tumour progression to the metastatic state.
UI - 11146623
AU - Mazumdar A; Wang RA; Mishra SK; Adam L; Bagheri-Yarmand R; Mandal M;
TI - Vadlamudi RK; Kumar R Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor.
SO - Nat Cell Biol 2001 Jan;3(1):30-7
AD - Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Activation of the heregulin/HER2 pathway in oestrogen receptor (ER)-positive breast-cancer cells leads to suppression of oestrogen-receptor element (ERE)-driven transcription and disruption of oestradiol responsiveness, and thus contributes to progression of tumours to more invasive phenotypes. Here we report the identification of metastatic-associated protein 1 (MTA1), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced by heregulin-beta1 (HRG). Stimulation of cells with HRG is accompanied by suppression of histone acetylation and enhancement of deacetylase activity. MTA1 is also a potent corepressor of ERE transcription, as it blocks the ability of oestradiol to stimulate ER-mediated transcription. The histone-deacetylase inhibitor trichostatin A blocks MTA1-mediated repression of ERE transcription. Furthermore, MTA1 directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER-alpha. Overexpression of MTA1 in breast-cancer cells is accompanied by enhancement of the ability of cells to invade and to grow in an anchorage-independent manner. HRG also promotes interaction of MTA1 with endogenous ER and association of MTA1 or HDAC with ERE-responsive target-gene promoters in vivo. These results identify ER-mediated transcription as a nuclear target of MTA1 and indicate that HDAC complexes associated with the MTA1 corepressor may mediate ER transcriptional repression by HRG.
UI - 11325822
AU - Martin MD; Fischbach K; Osborne CK; Mohsin SK; Allred DC; O'Connell P
TI - Loss of heterozygosity events impeding breast cancer metastasis contain the MTA1 gene.
SO - Cancer Res 2001 May 1;61(9):3578-80
AD - Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Breast cancer mortality is seldom attributable to the primary tumor, but rather to the presence of systemic (metastatic) disease. Axillary lymph node dissection can identify the presence of metastatic breast cancer cells and serves as a marker for systemic disease. Previous work in our laboratory determined that rates of loss of heterozygosity (LOH) of a 1.6-Mb region of chromosome 14q 31.2 is much higher in axillary lymph node-negative primary breast tumors than in axillary lymph node-positive primary breast tumors (P. O'Connell et al., J. NATL: Cancer INST:, 91: 1391-1397, 1999.). This unusual observation suggests that, whereas the LOH of this region promotes primary breast cancer formation, some gene(s) mapping to this 1.6-Mb region is rate-limiting for breast cancer metastasis. Thus, if primary breast cancers delete this region, their ability to metastasize decreases. To identify this gene(s), we have physically mapped this area of chromosome 14q, confirmed the position of two known genes and 13 other expressed sequence tags into this 1.6-Mb region. One of these, the metastasis-associated 1 (MTA1) gene, previously identified as a metastasis-promoting gene (Y. Toh et al., J. BIOL: CHEM:, 269: 22958-22963, 1994.), mapped to the center of our 1.6-Mb target region. Thus, MTA1 represents a strong candidate for this breast cancer metastasis-promoting gene.
UI - 12127160
AU - Hu XC; Loo WT; Chow LW
TI - E-cadherin promoter methylation can regulate its expression in invasive ductal breast cancer tissue in Chinese woman.
SO - Life Sci 2002 Aug 9;71(12):1397-404
AD - Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Pokfulam, Hong Kong, China.
Promoter methylation is an important mechanism of regulating E-cadherin expression. Methylation-specific PCR (MSP) assay was done to evaluate the promoter methylation status of E-cadherin gene in primary tumor samples from 23 cases of Chinese women with invasive ductal breast cancers. Western blotting assay was employed for E-cadherin and beta-actin expressions. Positive MSP results occurred in 26.1% (6/23) of primary tumor samples and none of four normal skin samples. These molecular events tended to occur in breast cancers associated with poor prognosis. Whereas the mean ratio of CDH1/beta-actin for six MSP-positive cases was 0.0290 +/- 0.0355, the mean ratio for 17 MSP-negative cases was 0.4726 +/- 0.5049 (P = 0.046). In conclusion, aberrant E-cadherin methylation preferentially occurs in invasive ductal breast cancer associated with poor prognosis and is one of the mechanisms of E-cadherin expression silence in breast cancers from Chinese women.
UI - 10847456
AU - Ferrero JM; Ramaioli A; Formento JL; Francoual M; Etienne MC; Peyrottes
TI - I; Ettore F; Leblanc-Talent P; Namer M; Milano G P53 determination alongside classical prognostic factors in node-negative breast cancer: an evaluation at more than 10-year follow-up.
SO - Ann Oncol 2000 Apr;11(4):393-7
AD - The Centre Antoine Lacassagne, Nice, France.
BACKGROUND: There is heterogeneity of methods and conflicting results concerning the prognostic value of p53 in node-negative breast cancer. The clinical value of a quantitative method for measuring tumoralp53 content still needs to be evaluated. PATIENTS AND METHODS: A long-term retrospective study was conducted on 297 node-negative patients with a median follow-up greater than 10 years (11 years, 101-172 months). Classic prognostic factors were considered including age, tumor size, histoprognostic grade and estradiol (ER) and progesterone receptors (PR). In addition, the value of p53 determination (immunoluminometric assay in tumor cytosol) was assessed for this long follow-up period. RESULTS: p53 concentrations were significantly linked to the histological grade (P = 0.001), to tumor size (P = 0.02) and ER status (P = 0.01). Higher p53 tumoral concentrations were found in tumors with large size, pejorative histological grade and negative ER status. In contrast, p53 tumoral concentrations were not influenced by menopausal or PR status. Multivariate Cox analysis demonstrates that tumor size was the only significant predictor of disease-free survival (P = 0.049) with a risk factor at 1.38. As regards specific survival, univariate Cox analysis indicates that p53 taken as a continuous variable is a significant predictor (P = 0.024) together with histological grade, tumor size and ER status. In a multivariate Cox analysis there were two significant and independent variables for predicting overall survival: tumor size (P = 0.031) and, ER status (P = 0.015) with the highest risk factor (RR = 2.14). CONCLUSIONS: The present investigation points out that the prognostic power of p53 tumor determination evaluated at more than 10 years median survival is not higher than the well-recognized classic prognostic factors in node-negative breast cancer. The present data highlight the need to assess the prognostic value of potentially new biological factors in node-negative breast cancer on cohorts of patients followed over periods in excess of 10 years.
UI - 11809257
AU - Ahr A; Karn T; Solbach C; Seiter T; Strebhardt K; Holtrich U; Kaufmann M
TI - Identification of high risk breast-cancer patients by gene expression profiling.
SO - Lancet 2002 Jan 12;359(9301):131-2
We previously used DNA array analyses in the molecular profiling of breast cancers. By cluster analysis of 55 patients, we identified a subpopulation of breast cancers-designated class A-that contained a high number of nodal-positive tumours and that had frequently developed distant metastases at the time of diagnosis. We have now analysed follow-up data from these patients. We found that, despite a median of only 23.5 months of follow-up, 11 of 22 patients in class A progressed to metastatic disease, and three of five patients classified as having a nodal status of N0 in this subpopulation developed distant metastases. Our analysis identifies breast-cancer patients with a high risk of disease recurrence, and could act as a first step towards improved patient-adapted therapy.
UI - 11936823
AU - Wohlfahrt J; Olsen JH; Melby M
TI - Breast cancer risk after childbirth in young women with family history (Denmark).
SO - Cancer Causes Control 2002 Mar;13(2):169-74
AD - Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen.
OBJECTIVE: The increased risk of breast cancer in women with family history of breast cancer (FHBC) might be reduced by early childbirths. However, childbirth induces a transient increase in risk in the first 5-10 years, which coincides with the relatively increased risk of family cases at a young age. The objective was to investigate this short-term change in risk according to FHBC. METHODS: We used a population-based cohort of 1.5 million Danish women. Between 1968 and 1990, 2770 incident cases of breast cancer below 40 years of age were identified in the Danish Cancer Register, of whom 276 (10%) had a FHBC. RESULTS: The first 5 years after a birth the short-term increase in risk was 30% (3-64%) larger in women with FHBC than without FHBC. After the first 5 years we observed no difference in the effect of a birth between women with and without FHBC. CONCLUSIONS: The adverse short-term effect of childbirthis stronger in women with FHBC.
UI - 12015032
AU - Li J; Xu L; He K; Guo W; Zhu X; Zheng Y; Xia P
TI - [Reversal of nomegestrol acetate on multidrug resistance in drug-resistant human breast cancer cell line MCF7/ADR]
SO - Zhonghua Zhong Liu Za Zhi 2002 Mar;24(2):129-32
AD - Department of Oncology, Xin Hua Hospital Cancer Center, Shanghai Second Medical University, Shanghai 200092, China.
OBJECTIVE: To study the reversal effect of nomegestrol acetate (NOM) on mutidrug resistance (MDR) in MCF7/ADR and its mechanism. METHODS: Using tetrazolium dye assay, effects of various concentrations of NOM on sensitivity to ADR in MCF7/ADR was studied. Expression of MDR related genes MDR1, glutathoine S-transferase Pi (GSTpi), Topoisomerase II alpha (Topo II alpha) and MDR related protein (MRP) were assayed by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry assay. Using flow cytometry (FCM), intracellular ADR concentration effects on cell cycle were observed. RESULTS: NOM significantly reversed MDR in MCF7/ADR. After NOM 20, 10 and 5 micromol/L treatment, the chemosensitivity to ADR increased to 21, 12 and 8 times. The reversal activity of NOM was stronger than that of the precursor compound megestrol acetate, and was comparable to that of verapamail. After treatment with NOM 5 mic