Last Modified: November 1, 2001
Table of Contents
CancerMail from the National Cancer Institute
UI - 20558157
AU - Austrup F; Uciechowski P; Eder C; Bockmann B; Suchy B; Driesel G; Jackel S; Kusiak I; Grill HJ; Giesing M
TI - Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients.
SO - Br J Cancer 2000 Dec;83(12):1664-73
AD - Institut fur Molekulare NanoTechnologie, Berghauser Str. 295, Recklinghausen, 45659, Germany.
The prognostic value of disseminated tumour cells derived from 353 breast cancer patients was evaluated. Disseminated tumour cells were purified from blood using a newly established method and nucleic acids were subsequently isolated. We investigated genomic imbalances (GI) such as mutation, amplification and loss of heterozygosity of 13 tumour suppressor genes and 2 proto-oncogenes using DNA from isolated minimal residual cancer cells. Significant correlations were found between genomic alterations of the DCC - and c-erbB-2 genes in disseminated breast cancer cells and actuarial relapse-free survival. Furthermore, increasing numbers of genomic imbalances measured in disseminated tumour cells were significantly associated with worse prognosis of recurrent disease. Logistic regression and Cox multivariate analysis led to the identification of genomic imbalances as an independent prognostic factor. Determination of disseminated tumour cells by genotyping of oncogenes and tumour suppressor genes seems not only to be a useful adjunct in follow up of carcinoma patients but provides also valuable additional individualized prognostic and predictive information in breast cancer patients beyond the TNM system. Copyright 2000 Cancer Research Campaign.
UI - 21198525
AU - Duell EJ; Millikan RC; Pittman GS; Winkel S; Lunn RM; Tse CK; Eaton A; Mohrenweiser HW; Newman B; Bell DA
TI - Polymorphisms in the DNA repair gene XRCC1 and breast cancer.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):217-22
AD - Department of Epidemiology, School of Public Health, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill 27599 -7400, USA.
X-ray repair cross complementing group 1 (XRCC1) encodes a protein involved in base excision repair. We examined the association of polymorphisms in XRCC1 (codon 194 Arg-->Trp and codon 399 Arg-->Gln) and breast cancer in the Carolina Breast Cancer Study, a population-based case-control study in North Carolina. No association was observed between XRCC1 codon 194 genotype and breast cancer, and odds ratios (ORs) were not modified by smoking or radiation exposure. A positive association for XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes compared with Arg/Arg was found among African Americans (253 cases, 266 controls; OR = 1.7, 95% confidence interval, 1.1-2.4) but not whites (386 cases, 381 controls; OR =1.0, 95% confidence interval, 0.8-1.4). Among African-American women, ORs for the duration of smoking were elevated among women with XRCC1 codon 399 Arg/Arg genotype (trend test; P < 0.001) but not Arg/Gln or Gln/Gln (P = 0.23). There was no difference in OR for smoking according to XRCC1 codon 399 genotype in white women. ORs for occupational exposure to ionizing radiation were stronger for African-American and white women with codon 399 Arg/Arg genotype. High-dose radiation to the chest was more strongly associated with breast cancer among white women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures. However, interpretation of our results is limited by incomplete knowledge regarding the biological function of XRCC1 alleles.
UI - 21198527
AU - Mitrunen K; Jourenkova N; Kataja V; Eskelinen M; Kosma VM; Benhamou S; Vainio H; Uusitupa M; Hirvonen A
TI - Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):229-36
AD - Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.
UI - 21261629
AU - Bisogna M; Calvano JE; Ho GH; Orlow I; Cordon-Cardo C; Borgen PI; Van Zee KJ
TI - Molecular analysis of the INK4A and INK4B gene loci in human breast cancer cell lines and primary carcinomas.
SO - Cancer Genet Cytogenet 2001 Mar;125(2):131-8
AD - Department of Surgery, The Breast Cancer Research Laboratory, Memorial Sloan-Kettering Cancer Center, 10021, New York, NY, USA.
The INK4A and INK4B loci are located at 9p21 and have been implicated in the tumorigenesis of various human malignancies. The INK4A gene encodes two cell cycle regulators, p16(INK4A) and ARF, while INK4B encodes p15(INK4B). Previously, we have shown that the p16(INK4) tumor suppressor was not mutated or deleted in primary breast carcinomas. However, primary and metastatic breast carcinomas exhibited a relative hypomethylation of p16(INK4A), which is associated with expression, compared to normal breast tissue. The present study was conducted to determine if inactivation of p15(INK4B) and INK4A exon 1beta (ARF) are common events in breast carcinoma. Mutational analysis was performed by PCR-SSCP, and mRNA expression was evaluated by RT-PCR. Methylation-specific PCR was used to determine the methylation status of the p15(INK4B) promoter. Our results demonstrate that the p15(INK4B) gene was altered in 3 (21%) of the 14 breast cell lines; one had a silent mutation and two had homozygous deletion of the gene. None of the cell lines showed methylation of p15(INK4B). Two (14%) cell lines had homozygous deletion of INK4A exon 1beta. All normal and malignant breast tissue samples were wild-type and non-methylated for p15(INK4B) and wild-type for exon 1beta. Our results show that these structurally and functionally related genes are not invariably affected together, and the most frequently observed alteration at the INK4A and INK4B loci in breast carcinoma appears to be p16(INK4A) hypomethylation.
UI - 21392454
AU - Krygier G; Lombardo K; Vargas C; Alvez I; Costa R; Ros M; Echenique M; Navarro V; Delgado L; Viola A; Muse A
TI - Familial uveal melanoma: report on three sibling cases.
SO - Br J Ophthalmol 2001 Aug;85(8):1007-8
UI - 21385728
AU - Silva J; Dominguez G; Silva JM; Garcia JM; Gallego I; Corbacho C; Provencio M; Espana P; Bonilla F
TI - Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer.
SO - Oncogene 2001 Jul 27;20(33):4586-90
AD - Department of Medical Oncology, Clinica Puerta de Hierro, E-28035-Madrid, Spain.
The INK4a/ARF locus encodes two unrelated cell cycle-regulatory proteins that both function in tumor suppression, p16INK4a and p14ARF. In human tumors including breast cancer, alterations affecting selectively p14ARF have been poorly analysed. We have performed a comprehensive analysis of the inactivation mechanisms (mutation, homozygous and hemizygous deletion, and promoter hypermethylation) in a large series of 100 primary breast carcinomas. RT-PCR showed expression variable of the p14ARF transcript, with 17% demonstrating overexpression and 26% demonstrating decreased expression. No detectable alterations were observed in the majority of cases with overexpressed p14ARF mRNA, but 77% of tumors with decreased expression presented at least one of these genetic/epigenetic alterations. Nevertheless, a statistically significant correlation was observed between decreased p14ARF expression and several poor prognostic parameters.
UI - 21385730
AU - Signori E; Bagni C; Papa S; Primerano B; Rinaldi M; Amaldi F; Fazio VM
TI - A somatic mutation in the 5'UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency.
SO - Oncogene 2001 Jul 27;20(33):4596-600
AD - Laboratory for Molecular Pathology and Gene Therapy, IRCCS H. Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, 71013, Italy.
Mutations in the 5' UTR which cause increment/decrement of translation efficiency have been recently described as a novel molecular mechanism of disease. Alterations in the consensus sequence for the translation initiation may promote context-dependent leaky scanning of ribosomes and/or initiation from a downstream AUG codon. Initiation of translation from a downstream in-frame AUG codon in BRCA1 gene was recently identified in normal cells and possibly in breast cancer. Here we present further insight into BRCA1 translational pathophysiology investigating the role of the canonical structure of the initiation consensus sequence of BRCA1. We have analysed the effect of a somatic point mutation (117 G>C) in position -3 with respect to the AUG of the BRCA1 gene, identified in a highly aggressive sporadic breast cancer. We constructed chimeric genes encoding the luciferase reporter sequence downstream of the wild type or the mutated BRCA1 5'UTR. These transcripts were tested for their activity in in vitro and in vivo systems. In in vitro transcription/translation assays the estimated translation efficiency of the construct with the mutated BRCA1 5'UTR was 30-50% lower than that with the wild type BRCA1 5'UTR. The same chimeric genes were analysed for their expression in vivo by transient transfection in human cells. While the two constructs were equally transcribed, the plasmid carrying the mutated sequence produced 70% less luciferase activity compared to the wild type sequence. Finally, to obtain a direct evaluation on translational efficiency in vivo, we analysed mRNA translation on translationally active and non-active ribosomes separated from transfected cells. Mutant mRNA was partially localized in subpolysomal particles analytically confirming a polysome recruitment defect. Thus, characterization of BRCA1 5'UTR and translation efficiency seems to provide new insight into BRCA1 role in breast and ovarian cancer pathogenesis.
UI - 21388218
AU - Schwirzke M; Evtimova V; Burtscher H; Jarsch M; Tarin D; Weidle UH
TI - Identification of metastasis-associated genes by transcriptional profiling of a pair of metastatic versus non-metastatic human mammary carcinoma cell lines.
SO - Anticancer Res 2001 May-Jun;21(3B):1771-6
AD - Roche Diagnostics GmbH, Division Pharma, Penzberg, Germany.
Cell lines 4A4 and 2C5 are the respective metastatic and non-metastatic variants of the human mammary carcinoma cell line MDA-MB-435 in the nude mouse system. We compared the transcriptional profile of approximately 5000 full-length genies using the Affymetrix HuGene FL Array technology. We have shown that the metastatic phenotype is mediated by different functional categories of genes, e.g. genes involved in immune response, genes responsible for tumor antigens, genes involved in migration and invasion, genes involved in mediating signal transduction, genes responsible for transcription factors, genes involved in phospholipid signaling, genes involved in modulation of extracellular matrix and cytoskeleton, genes with a cell-type specific mode of expression and genes which do not fit into the subclasses as defined above. Our results suggest an important role of Autocrine Motility Factor (AMF) as a mediator of metastasis in this system.
UI - 21388226
AU - Yang Q; Sakurai T; Yoshimura G; Mori I; Nakamura M; Nakamura Y; Suzuma T; Tamaki T; Umemura T; Kakudo K
TI - Hypermethylation does not account for the frequent loss of the retinoic acid receptor beta2 in breast carcinoma.
SO - Anticancer Res 2001 May-Jun;21(3B):1829-33
AD - Department of Surgery, Affiliated Kihoku Hospital, Wakayama Medical University School of Medicine, Wakayama City, Japan. firstname.lastname@example.org
Hypermethylation of the retinoic acid receptor (RAR) beta2 has been detected in breast cancer cell lines and is known to repress the level of RAR beta2 transcription. RAR beta2 mRNA loss has often been detected in breast cancer tumors, whether promoter region methylation of the RAR beta2 gene accounts for its loss is still unknown. We examined the methylation status of RAR beta2 in breast tumors; 21 out of 50 (42%) breast tumors showed RAR beta2 hypermethylation. RT-PCR analysis showed a complete loss of RAR beta2 mRNA expression in 15 out of 43 (35%) breast tumors. No correlation between the hypermethylation and RAR beta2 loss was found, suggesting that hypermethylation is not fully responsible for the loss of expression of the RAR beta2 gene during breast tumorigenesis.
UI - 21394109
AU - Glasow A; Horn LC; Taymans SE; Stratakis CA; Kelly PA; Kohler U; Gillespie J; Vonderhaar BK; Bornstein SR
TI - Mutational analysis of the PRL receptor gene in human breast tumors with differential PRL receptor protein expression.
SO - J Clin Endocrinol Metab 2001 Aug;86(8):3826-32
AD - Children's Hospital, University of Leipzig, 04317 Leipzig, Germany. email@example.com
PRL is a major growth and differentiating hormone in the human breast, with activation of the PRL-PRL receptor complex increasingly recognized as an important mechanism in the induction and progression of mammary tumors. Although constitutive activation of various hormone and growth factor receptors is newly recognized as a common cause of tumor development, the PRL receptor gene has not been analyzed for similar aberrations in breast and other tumors. Therefore, using bacterial artificial chromosomes containing the PRL receptor gene and intron-spanning PCR, we determined the exon-surrounding intron sequences providing primers for the first analysis of the entire coding region of the human PRL receptor gene. We examined the presence of PRL receptor in 41 breast tumors by immunohistochemistry and attempted a correlation of its expression to pathological grading of the disease. Then tumor cells were isolated by laser capture microdissection to examine DNA from 30 patients for PRL receptor mutations. The PRL receptor immunoreactive score did not correlate to the tumor size, histopathological grading, age, or family history of patients. PRL receptor immunoreactivity was predominantly found in steroid hormone receptor-positive tumors, but without overall correlation of immunoreactive score. In both PRL receptor-positive and PRL receptor- negative breast cancer cells, direct sequencing of the coding sequence of the PRL receptor gene did not detect any somatic or hereditary gene aberrations. In conclusion, PRL receptor mutations do not appear to be common in human breast cancer, suggesting that constitutive activation of the PRL receptor can be excluded as a major cause of mammary tumor genesis. The molecular structure of the PRL receptor seems to remain intact in tumor tissue, and systemic and local production of PRL may participate in tumor cell growth and proliferation through functional receptors.
UI - 21391956
AU - Castro-Rivera E; Samudio I; Safe S
TI - Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements.
SO - J Biol Chem 2001 Aug 17;276(33):30853-61
AD - Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station, Texas 77843-4466, USA.
Cyclin D1 gene expression is induced by 17beta-estradiol (E2) in human breast cancer cells and is important for progression of cells through the G(1) phase of the cell cycle. The mechanism of activation of cyclin D1 is mitogen- and cell context-dependent, and this study describes the role of multiple promoter elements required for induction of cyclin D1 by E2 in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Transcriptional activation of cyclin D1 by E2 was dependent, in part, on a proximal cAMP-response element at -66, and this was linked to induction of protein kinase A-dependent pathways. These results contrasted to a recent report showing that induction of cyclin D1 by E2 in ER-positive MCF-7 and HeLa cells was due to up-regulation of c-jun and subsequent interaction of c-Jun-ATF-2 with the CRE. Moreover, further examination of the proximal region of the cyclin D1 promoter showed that three GC-rich Sp1-binding sites at -143 to -110 were also E2-responsive, and interaction of ERalpha and Sp1 proteins at these sites was confirmed by electromobility shift and chromatin immunoprecipitation assays. Thus, induction of cyclin D1 by E2 in ZR-75 cells is regulated through nuclear ERalpha/Sp1 and epigenetic protein kinase A activation pathways, and our results suggest that this mechanism may be cell context-dependent even among ER-positive breast cancer cell lines.
UI - 21397933
AU - Gruvberger S; Ringner M; Chen Y; Panavally S; Saal LH; Borg A; Ferno M; Peterson C; Meltzer PS
TI - Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns.
SO - Cancer Res 2001 Aug 15;61(16):5979-84
AD - Department of Oncology, Lund University, SE-221 00 Lund, Sweden.
To investigate the phenotype associated with estrogen receptor alpha (ER) expression in breast carcinoma, gene expression profiles of 58 node-negative breast carcinomas discordant for ER status were determined using DNA microarray technology. Using artificial neural networks as well as standard hierarchical clustering techniques, the tumors could be classified according to ER status, and a list of genes which discriminate tumors according to ER status was generated. The artificial neural networks could accurately predict ER status even when excluding top discriminator genes, including ER itself. By reference to the serial analysis of gene expression database, we found that only a small proportion of the 100 most important ER discriminator genes were also regulated by estradiol in MCF-7 cells. The results provide evidence that ER+ and ER- tumors display remarkably different gene-expression phenotypes not solely explained by differences in estrogen responsiveness.
UI - 21241494
AU - Chan JK; Wong CS
TI - Loss of E-cadherin is the fundamental defect in diffuse-type gastric carcinoma and infiltrating lobular carcinoma of the breast.
SO - Adv Anat Pathol 2001 May;8(3):165-72
AD - Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.
UI - 21301539
AU - Dialyna IA; Arvanitis DA; Spandidos DA
TI - Genetic polymorphisms and transcriptional pattern analysis of CYP1A1, AhR, GSTM1, GSTP1 and GSTT1 genes in breast cancer.
SO - Int J Mol Med 2001 Jul;8(1):79-87
AD - Department of Virology, Medical School, University of Crete, Heraklion, Crete, Greece.
In order to detect the contribution of cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR), glutathione S-transferases M1 (GSTM1), P1 (GSTP1), and T1 (GSTT1) genes in breast cancer, genetic analysis was performed, as well as transcriptional analysis in sporadic primary tumours and corresponding adjacent normal tissues from the same patient. CYP1A1 3'-untranslated region (3'-UTR) termed as m1 (MspI) polymorphism and the null(-) deletions of both GSTM1 and GSTT1 genes were examined in genomic DNA from blood samples of 207 female breast cancer patients and 171 age and sex matched controls. The frequencies of the m1 genotype of the CYP1A1 gene in cases and controls were 0.13 and 0.15, while the frequencies of homozygotes with GSTM1(-) were 0.52, in each, and for homozygotes with GSTT1(-) were 0.14 and 0.10, respectively. Statistical analysis of these genotypes in combinations did not reveal any significant difference between the breast cancer population and the control group. Expression of mRNA levels of CYP1A1, GSTM1, GSTP1, GSTT1 and AhR genes in 31 breast cancer patients, revealed inter-individual variation in an independent manner to patient age, genotype, or tumour stage. Eighty-seven percent of the tumour specimens tested were deregulated, compared to their normal counterparts, in at least one locus. Up-regulation of CYP1A1 was observed only when one of the GSTM1 or GSTP1 was down-regulated while the other remained constant. Genotyping analysis did not show any correlation to breast cancer risk. However, RT-PCR analysis provided evidence that CYP1A1, AhR, GSTM1, GSTP1 and GSTT1 genes are frequently deregulated in breast cancer and could be used as molecular biomarkers for better clinical management of such patients, with respect to chemotherapy.
UI - 21302031
AU - Hennighausen L
TI - The genetics and pathology of mouse mammary cancer.
SO - Semin Cancer Biol 2001 Jun;11(3):239-44
UI - 21341624
AU - Costa SC; Nascimento LS; Ferreira FJ; Mattos PS; Camara-Lopes LH; Ward LS
TI - Lack of mutations of exon 2 of the MEN1 gene in endocrine and nonendocrine sporadic tumors.
SO - Braz J Med Biol Res 2001 Jul;34(7):861-5
AD - Departamento de Clinica Medica, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
In addition to the mutations that underlie most cases of the multiple endocrine neoplasia type 1 (MEN1) syndrome, somatic mutations of the MEN1 gene have also been described in sporadic tumors like gastrinomas, insulinomas and bronchial carcinoid neoplasm. We examined exon 2 of this gene, where most of the mutations have been described, in 148 endocrine and nonendocrine sporadic tumors. DNA was obtained by phenol/chloroform extraction and ethanol precipitation from 92 formalin-fixed, paraffin-embedded samples, and from 40 fresh tumor tissue samples. We used 5 pairs of primers to encompass the complete coding sequence of exon 2 of the MEN1 gene that was screened by the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) technique in 78 sporadic thyroid cancers: 28 follicular adenomas, 35 papillary carcinomas, 14 follicular carcinomas, and 1 anaplastic thyroid carcinoma. We also examined 46 adrenal lesions (3 hyperplasias, 3 adenomas and 35 adrenocortical carcinomas, 2 pheochromocytomas, 2 ganglioneuroblastomas, and 1 lymphoma) and 24 breast cancers (6 noninvasive, 16 infiltrating ductal, and 2 invasive lobular tumors). The PCR product of 5 tumors suspected to present band shifts by SSCP was cloned. Direct sense and antisense sequencing did not identify mutations. These results suggest that the MEN1 gene is not important in breast, thyroid or adrenal sporadic tumorigenesis. Because the frequency of mutations varies significantly among tumor subgroups and allelic deletions are frequently observed at 11q13 in thyroid and adrenal cancers, another tumor suppressor gene residing in this region is likely to be involved in the tumorigenesis of these neoplasms.
UI - 21345032
AU - Piura B; Rabinovich A; Yanai-Inbar I
TI - Three primary malignancies related to BRCA mutation successively occurring in a BRCA1 185delAG mutation carrier.
SO - Eur J Obstet Gynecol Reprod Biol 2001 Aug;97(2):241-4
AD - Unit of Gynecologic Oncology, Department of Obstetrics and Gynecology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 151, 84101, Beer-Sheva, Israel. firstname.lastname@example.org
The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene (the Ashkenazi mutations) have been found to be significantly more common among Jews of eastern European ancestry (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1 in 300, 0.12-0.33%). Carriers of these mutations, especially the BRCA1 185delAG mutation, have a significantly increased lifetime risk of breast and ovarian carcinoma and other carcinomas as compared to non-carriers. A case of three primary malignancies related to the BRCA1 185delAG mutation successively occurring in a carrier of this mutation, is described. The patient successively developed breast carcinoma, ovarian micropapillary serous carcinoma and peritoneal papillary serous carcinoma. Immunohistochemical staining results have indicated that these tumors are three separate primary malignancies. This case illustrates that ovarian serous borderline tumors (including micropapillary serous carcinoma) and peritoneal papillary serous carcinomas should be considered, like breast and ovarian carcinomas, tumors expressed in BRCA mutation carriers.
UI - 21371754
AU - Yousef GM; Bharaj BS; Yu H; Poulopoulos J; Diamandis EP
TI - Sequence analysis of the human kallikrein gene locus identifies a unique polymorphic minisatellite element.
SO - Biochem Biophys Res Commun 2001 Aug 3;285(5):1321-9
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Minisatellites are repetitive sequences of DNA that are present throughout the genome. Although the origin and function of these minisatellites is still unknown, they found clinical applications as markers of many diseases, including cancer. Also, they are useful tools for DNA fingerprinting and linkage analysis. Kallikreins are serine proteases that appear to be involved in many diseases including brain disorders and malignancy. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. In this study, we examined the kallikrein locus ( approximately 300 Kb) for all known repeat elements. About 50% of this genomic area is occupied by different repeat elements. We also identified unique minisatellite elements that are restricted to chromosome 19q13. Ten clusters of these minisatellites are distributed along the locus on either DNA strand. The clusters are located in the promoters and enhancers of genes, in introns, and in untranslated regions of the mRNA. Analysis of these elements indicates that they are polymorphic, thus they can be useful in linkage analysis and DNA fingerprinting. Our preliminary results indicate also that the distribution of the different alleles of these minisatellites might be associated with malignancy. Copyright 2001 Academic Press.
UI - 21403443
AU - Manning AP; Abelovich D; Ghadirian P; Lambert JA; Frappier D; Provencher D; Robidoux A; Peretz T; Narod SA; Mes-Masson AM; Foulkes WD; Wang T; Morgan K; Fujiwara TM; Tonin PN
TI - Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families.
SO - Hum Hered 2001;52(2):116-20
AD - McGill University Centre Research Institute, Montreal, Canada.
The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.
UI - 21407786
AU - Walker GE; Wilson EM; Powell D; Oh Y
TI - Butyrate, a histone deacetylase inhibitor, activates the human IGF binding protein-3 promoter in breast cancer cells: molecular mechanism involves an Sp1/Sp3 multiprotein complex.
SO - Endocrinology 2001 Sep;142(9):3817-27
AD - Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Specific cell growth stimulators and inhibitors regulate IGF binding protein-3 (IGFBP-3), where in turn IGFBP-3 mediates their biological effects. The molecular mechanism(s) by which these factors regulate IGFBP-3 are unknown. Sodium butyrate, a histone deacetylase inhibitor causing growth arrest and differentiation, increases IGFBP-3 expression. We investigated the molecular mechanism of this induction using an IGFBP-3 promoter reporter system in MCF-7 and Hs578T breast cancer cells. IGFBP-3 promoter activity was induced up to 40-fold following a 24-h treatment with sodium butyrate and 46-fold in cells treated with trichostatin A, a pure histone deacetylase inhibitor. Deletion analysis of the IGFBP-3 promoter identified key sodium butyrate-responsive element(s) to a 45-bp region containing consensus binding sites for Sp1 and activating protein-2. Sp1 binding to the Sp1 site and Sp3 to the activating protein-2/GA-box played a functional role in sodium butyrate's activation of the IGFBP-3 promoter, however, with no change in binding direct sodium butyrate regulation was attributed to cofactors. The histone acetyltransferase p300 and histone deacetylase-1 were identified in multiprotein complexes containing DNA bound Sp1 and Sp3, with p300 accumulating following sodium butyrate treatment. Taken together, these data suggest that sodium butyrate increases IGFBP-3 expression by activating the IGFBP-3 promoter via an Sp1/Sp3 multiprotein complex, a mechanism that may be important for other key regulators of IGFBP-3.
UI - 21413568
AU - Backlund MG; Trasti SL; Backlund DC; Cressman VL; Godfrey V; Koller BH
TI - Impact of ionizing radiation and genetic background on mammary tumorigenesis in p53-deficient mice.
SO - Cancer Res 2001 Sep 1;61(17):6577-82
AD - Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Loss of p53 function is known to compromise cell cycle regulation, inductionof apoptosis, and DNA damage repair and can facilitate neoplastic transformation of cells. Mutations in the p53 gene are identified frequently in breast carcinomas. Li-Fraumeni patients inheriting a mutant p53 allele have an increased risk for developing tumors including breast cancer. Although mouse lines carrying mutations in the p53 gene have been generated, they die primarily of lymphoma and thus to date provide a limited model for the study of this disease and the role of p53 in nonfamilial breast cancer. An increasing body of literature suggests that the incidence of various tumors is determined largely by the genetic background on which mutations are studied. In addition, population studies and studies in animals suggest that environmental factors, together with genetic factors, determine overall risk for development of specific types of tumors. We therefore examined the impact of genetic background together with exposure to ionizing radiation on the development of tumors, particularly mammary tumors, in p53-deficient animals. We report here that modifier alleles present in the BALB/c strain increase the incidence of hemangiosarcomas [15 of 53 (28.3%); P = 0.0007] in p53(-/-) mice above rates reported previously in p53(-/-) mice on a mixed background as compared to the incidence observed in DBA/p53(-/-) mice. However, no increase in the frequency of mammary tumors is seen in these mice or in p53(-/-) DBA/2 animals, nor was an increase in mammary tumors observed in the DBA/2 p53(+/-) mice, even after exposure to 5 Gy of whole-body ionizing radiation. In contrast, a significant increase in the incidence of mammary tumors was observed in similarly treated BALB/c p53(+/-) mice (37.3% versus 6.8%; P = 0.0007). This was accompanied by a comparable decrease in the incidence of lymphomas. These results show that environmental agents together with genetic factors can increase the frequency and decrease the latency of mammary tumors, leading to an incidence similar to that observed in Li-Fraumeni syndrome. Furthermore, it suggests that the risk of development of a particular type of tumor by individuals deficient in p53 after exposure to damaging agents can be influenced by modifier alleles.
UI - 21148292
AU - Lewis MT
TI - Homeobox genes in mammary gland development and neoplasia.
SO - Breast Cancer Res 2000;2(3):158-69
AD - Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. email@example.com
Both normal development and neoplastic progression involve cellular transitions from one physiological state to another. Whereas much is being discovered about signal transduction networks involved in regulating these transitions, little progress has been made in identifying the higher order genetic determinants that establish and maintain mammary cell identity and dictate cell type-specific responses to mammotropic signals. Homeobox genes are a large superfamily of genes whose members function in establishing and maintaining cell fate and cell identity throughout embryonic development. Recent genetic and expression analyses strongly suggest that homeobox genes may perform similar functions at specific developmental transition points in the mammary gland. These analyses also suggest that homeobox genes may play a contributory or causal role in breast cancer.
UI - 21148299
AU - Andrechek ER; Muller WJ
TI - Tyrosine kinase signalling in breast cancer: tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer.
SO - Breast Cancer Res 2000;2(3):211-6
AD - Institute for Molecular Biology and Biotechnology, Department of Biology, McMaster University, Hamilton, Ontario, Canada.
The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes.
UI - 97195534
AU - Serova OM; Mazoyer S; Puget N; Dubois V; Tonin P; Shugart YY; Goldgar D; Narod SA; Lynch HT; Lenoir GM
TI - Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes?
SO - Am J Hum Genet 1997 Mar;60(3):486-95
AD - International Agency for Research on Cancer, Lyon, France.
To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene.
UI - 21060593
AU - Gorski B; Byrski T; Huzarski T; Jakubowska A; Menkiszak J; Gronwald J; Pluzanska A; Bebenek M; Fischer-Maliszewska L; Grzybowska E; Narod SA; Lubinski J
TI - Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
SO - Am J Hum Genet 2000 Jun;66(6):1963-8
AD - Department of Genetics and Pathology, Hereditary Cancer Center, 70-115 Szczecin, Poland.
We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.
UI - 21090525
AU - de los Rios P; Jack E; Kuperstein G; Lynch H; Lubinski J; Narod SA
TI - Founder mutations of BRCA1 and BRCA2 in North American families of Polish origin that are affected with breast cancer.
SO - Am J Hum Genet 2001 Feb;68(2):546
UI - 21249655
AU - Newman LA; Kuerer HM; Hunt KK; Vlastos G; Ames FC; Ross MI; Singletary SE
TI - Educational review: role of the surgeon in hereditary breast cancer.
SO - Ann Surg Oncol 2001 May;8(4):368-78
AD - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.
UI - 21259364
AU - Kotlan B; Simsa P; Gruel N; Foldi J; Fridman WH; Petranyi G; Teillaud JL
TI - A scFv phage display mini library generated from the immunoglobulin repertoire of breast medullary carcinoma infiltrating B lymphocytes.
SO - Dis Markers 2000;16(1-2):25-7
AD - National Institute of Haematology and Immunology, Budapest 1113, Daroczi Street 24, P.O.B. H-1519, Hungary. firstname.lastname@example.org
UI - 21275464
AU - Collins C; Volik S; Kowbel D; Ginzinger D; Ylstra B; Cloutier T; Hawkins T; Predki P; Martin C; Wernick M; Kuo WL; Alberts A; Gray JW
TI - Comprehensive genome sequence analysis of a breast cancer amplicon.
SO - Genome Res 2001 Jun;11(6):1034-42
AD - University of California San Francisco Cancer Center, San Francisco, California 94143-0808, USA. email@example.com
Gene amplification occurs in most solid tumors and is associated with poor prognosis. Amplification of 20q13.2 is common to several tumor types including breast cancer. The 1 Mb of sequence spanning the 20q13.2 breast cancer amplicon is one of the most exhaustively studied segments of the human genome. These studies have included amplicon mapping by comparative genomic hybridization (CGH), fluorescent in-situ hybridization (FISH), array-CGH, quantitative microsatellite analysis (QUMA), and functional genomic studies. Together these studies revealed a complex amplicon structure suggesting the presence of at least two driver genes in some tumors. One of these, ZNF217, is capable of immortalizing human mammary epithelial cells (HMEC) when overexpressed. In addition, we now report the sequencing of this region in human and mouse, and on quantitative expression studies in tumors. Amplicon localization now is straightforward and the availability of human and mouse genomic sequence facilitates their functional analysis. However, comprehensive annotation of megabase-scale regions requires integration of vast amounts of information. We present a system for integrative analysis and demonstrate its utility on 1.2 Mb of sequence spanning the 20q13.2 breast cancer amplicon and 865 kb of syntenic murine sequence. We integrate tumor genome copy number measurements with exhaustive genome landscape mapping, showing that amplicon boundaries are associated with maxima in repetitive element density and a region of evolutionary instability. This integration of comprehensive sequence annotation, quantitative expression analysis, and tumor amplicon boundaries provide evidence for an additional driver gene prefoldin 4 (PFDN4), coregulated genes, conserved noncoding regions, and associate repetitive elements with regions of genomic instability at this locus.
UI - 21279546
AU - Pinzani P; Orlando C; Raggi CC; Distante V; Valanzano R; Tricarico C; Maggi M; Serio M; Pazzagli M
TI - Type-2 somatostatin receptor mRNA levels in breast and colon cancer determined by a quantitative RT-PCR assay based on dual label fluorogenic probe and the TaqMan technology.
SO - Regul Pept 2001 Jun 15;99(2-3):79-86
AD - Clinical Biochemistry, Department of Clinical Physiopathology, University of Florence, viale Pieraccini 6, 50139, Florence, Italy.
We reported previously that the expression of type 2 somatostatin receptor (sst2) was positively related to patient outcome in the childhood tumor neuroblastoma. To quantitate the expression of mRNA sst2 expression, we used a competitive RT-PCR assay. To improve the practicability of this measurement and its applicability to large groups of patients, we present here an original 'real-time' quantitative RT-PCR method, based on a dual-labeled fluorogenic probe and the TaqMan technology. By this method, we have measured sst2 mRNA expression in 24 breast cancer samples and 26 colon carcinomas as well as on the corresponding non-adjacent non-neoplastic tissue of the same patients. The proposed method has a dynamic range of 4 x 10(4) to 4 x 10(8) molecules of sst2 mRNA. The intra-assay precision of the test, evaluated as signal detection variability, was 2.4%. Accuracy, evaluated by the addition of standard RNA to unknown samples, provided a mean recovery of 98+/-2%. A significant correlation has been observed in a study performed in 24 neuroblastoma samples measured both with the proposed method and with a competitive RT-PCR assay (r=0.913, p<0.001). In our preliminary clinical study, no significant differences were observed in sst2 mRNA levels between normal and tumor specimens in both colorectal (normal tissue 5.1 x 10(7)+/-2.0 x 10(7) molecules/microg total RNA, cancer tissue 9.7 x 10(7)+/-4.2 x 10(7)) and breast tumors (normal tissue 5.5 x 10(8)+/-2.0 x 10(8), cancer tissue 4.4 x 10(8)+/-3,7 x 10(8)).However, in colorectal cancer, sst2 mRNA values of subjects with high circulating carcinoembryonic antigen (CEA) levels (>5 ng/ml) were statistically lower (2.3 x 10(7)+/-6.2 x 10(6) molecules/, microg total RNA; p<0.05) than those of subjects with low CEA concentration (1.4 x 10(8)+/-6.7 x 10(7)). Also, the sst2 mRNA ratio between normal and tumor tissue (N/T ratio) resulted significantly inversely related to CEA levels.In breast cancer, a significant difference was found between the mean N/T ratio of negative (below 10 fmol/mg protein) and positive estrogen receptor tumors (p<0.05). Analogous results were found selecting breast tumors on the basis of the progesterone receptor status (p<0.05). The proposed method is accurate, precise, sensitive and less labor-intensive than the competitive RT-PCR assay. For a correct evaluation of sst2 mRNA expression, it seems very important to measure the sst2 expression both in tumor and in the non-tumoral non-adjacent tumor specimens.
UI - 21303198
AU - Chang J; Hilsenbeck SG; Sng JH; Wong J; Ragu GC
TI - Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients.
SO - Clin Cancer Res 2001 Jun;7(6):1739-42
AD - Breast Center, Baylor College of Medicine, Houston Texas 77030, and Departments of Medical Oncology and Pathology, National University of Singapore, Singapore 0511. firstname.lastname@example.org
PURPOSE: Risk calculations for carrying BRCA1/BRCA2 mutations are based on family history and the age of onset of cancers. However, women may carry these deleterious mutations without a strong family history. Additional criteria for risk estimation would be of value. It has been recently established that BRCA1-associated breast cancers are associated with poor tumor differentiation (TD3) and estrogen receptor (ER) negativity. The aim of this study is to determine whether morphological features of breast cancers in premenopausal patients (age < 45 years) could determine additional women who may benefit from BRCA1 screening. EXPERIMENTAL DESIGN: In a prospective, systematic study of 76 consecutive breast cancer patients (age < 45 years), genomic DNA was obtained from peripheral blood, and eight mutations in BRCA1 (10.5%) were found. Archival paraffin-embedded breast cancer specimens were then analyzed for tumor differentiation and ER status. RESULTS: In patients < 45 years of age, 25% (6 of 24) of ER-negative and TD3 breast cancers were found to harbor mutations in BRCA1. Only 5.6% (2 of 36) of BRCA1-associated breast cancers did not have this morphological profile, compared with 94.4% (34 of 36) patients without BRCA1 mutations, giving an odds ratio of 5.67 (95% confidence interval, 1.04-32; P = 0.05). Finally, only one patient with BRCA1 mutations had a significant family history. CONCLUSIONS: In patients with early-onset breast cancer, the use of mor