Biomedical subjects

Daniel Birnbaum

Publications and source records attributed to Daniel Birnbaum.

At least 55 records · Page 3Linked to original sources

PubMed2004

Basal and luminal breast cancers: basic or luminous? (review).

Three major, fast developing lines of research are elucidating the biology of the mammary gland and its malignant transformation: phenotypical analyses of epithelial cells and mammary proliferative lesions, the identification, purification and characterization of mammary stem cells and breast cancer-initiating cells, and gene expression profiling studies using high-throughput microarray technologies. These three approaches are providing a flux of new, increasingly coherent information and are improving cellular and molecular models of breast epithelium and its malignancies. A new conceptual framework is emerging, altering viewpoints on the differentiation and transformation of the mammary epithelial cells. The combined effects of these progresses on our understanding of breast cancer biology should have major consequences on the way this disease is managed.

Basement Membrane↗

PubMed2003

Loss of FHIT protein expression is a marker of adverse evolution in good prognosis localized breast cancer.

The FHIT tumor suppressor gene, which encompasses the fragile site FRA3B at 3p14.2, is altered frequently in many types of human cancers. To determine its importance as a prognostic marker in breast cancer, the expression of the FHIT protein was studied in a series of 452 breast carcinomas by using immunohistochemistry on sections of tissue microarrays. Three distinct levels of FHIT expression were observed: in 154 cases (34.1%) expression was unchanged as compared to normal level; in 78 (17.2%) no expression was found; in the remaining 220 cases (48.7%), expression was intermediate. Overall, two-thirds of the cases had abnormal levels of the protein. Absence of FHIT was significantly associated with a higher grade (p < 0.01) and absence of hormone receptors (p < 0.001). The patients were separated into Group I (153 node-negative good prognosis patients who did not receive adjuvant chemotherapy) and Group II (226 high-risk patients treated by adjuvant chemotherapy) according to the St.-Gallen conference consensus. The median follow-up was 48 months. Among Group I but not Group II patients, a multivariate analysis showed that FHIT expression was significantly associated with disease-free survival. The relative risk of recurrence for FHIT-negative Group I patients was 2.37 (1.21-4.64; p = 0.03). Thus, among the patients who present with tumors of apparent good prognosis, FHIT is an independent prognostic factor that distinguishes a subgroup of patients who could benefit from adjuvant treatment.

Acid Anhydride Hydrolases↗

PubMed2003

Small lymphocytic lymphoma, marginal zone B-cell lymphoma, and mantle cell lymphoma exhibit distinct gene-expression profiles allowing molecular diagnosis.

Non-germinal center small B-cell lymphomas represent a heterogeneous group of non-Hodgkin lymphomas, the most frequent histologic subtypes being small lymphocytic lymphoma (SLL), splenic marginal zone B-cell lymphoma (MZL), and mantle cell lymphoma (MCL). In order to identify genomic signatures specific for each disease, we analyzed 128 primary tumors using high-density microarrays. Several clusters of genes significantly discriminated the 3 histologic subtypes. Genes associated with cell adhesion, angiogenesis, and inhibition of apoptosis were up-regulated in SLL. Genes associated with intracellular signaling via the AKT1 pathway were up-regulated in splenic MZL. Genes associated with cell cycle control and multidrug resistance were up-regulated in MCL. Using 44 genes selected within the gene clusters discriminant for the 3 lymphoma subtypes, we generated a class prediction score that allowed us to classify the 3 entities in 96% of the cases, including borderline cases. Whereas specific transcriptional profiles easily distinguished all MZL samples, SLL samples, and most of the MCL samples into separate groups, few MCL cases exhibited MZL-type transcriptional profiles. This study demonstrates that SLL, splenic MZL, and MCL possess specific transcriptional profiles that may be relevant to the pathogenesis and the diagnosis of these histologic subtypes.

Biopsy↗

PubMed2003

TACC1-chTOG-Aurora A protein complex in breast cancer.

The three human TACC (transforming acidic coiled-coil) genes encode a family of proteins with poorly defined functions that are suspected to play a role in oncogenesis. A Xenopus TACC homolog called Maskin is involved in translational control, while Drosophila D-TACC interacts with the microtubule-associated protein MSPS (Mini SPindleS) to ensure proper dynamics of spindle pole microtubules during cell division. We have delineated here the interactions of TACC1 with four proteins, namely the microtubule-associated chTOG (colonic and hepatic tumor-overexpressed gene) protein (ortholog of Drosophila MSPS), the adaptor protein TRAP (tudor repeat associator with PCTAIRE2), the mitotic serine/threonine kinase Aurora A and the mRNA regulator LSM7 (Like-Sm protein 7). To measure the relevance of the TACC1-associated complex in human cancer we have examined the expression of the three TACC, chTOG and Aurora A in breast cancer using immunohistochemistry on tissue microarrays. We show that expressions of TACC1, TACC2, TACC3 and Aurora A are significantly correlated and downregulated in a subset of breast tumors. Using siRNAs, we further show that depletion of chTOG and, to a lesser extent of TACC1, perturbates cell division. We propose that TACC proteins, which we also named 'Taxins', control mRNA translation and cell division in conjunction with microtubule organization and in association with chTOG and Aurora A, and that these complexes and cell processes may be affected during mammary gland oncogenesis.

Aurora Kinase A↗

PubMed2003

FOP-FGFR1 tyrosine kinase, the product of a t(6;8) translocation, induces a fatal myeloproliferative disease in mice.

Constitutive activation of aberrant fibroblast growth factor receptor 1 (FGFR1) kinase as a consequence of gene fusion such as FOP-FGFR1 associated with t(6; 8)(q27;p11-12) translocation, is the hallmark of an atypical aggressive stem cell myeloproliferative disorder (MPD) in humans. In this study, we show that expression of FOP-FGFR1 in primary bone marrow cells induced by retroviral transduction generates a MPD in mice. Constitutive FOP-FGFR1 kinase activity was both essential and sufficient to cause a chronic myeloproliferative syndrome in the murine bone marrow transplantation model. In contrast to the human disorder, lymphoproliferation and progression to acute phase were not observed. Lymphoid symptoms, however, appeared when onset of the disease was delayed as the result of mutation of FOP-FGFR1 at tyrosine 511, the phospholipase C gamma (PLCgamma) binding site.

Animals↗

PubMed2003

Genetic variability in MCF-7 sublines: evidence of rapid genomic and RNA expression profile modifications.

BACKGROUND: Both phenotypic and cytogenetic variability have been reported for clones of breast carcinoma cell lines but have not been comprehensively studied. Despite this, cell lines such as MCF-7 cells are extensively used as model systems. METHODS: In this work we documented, using CGH and RNA expression profiles, the genetic variability at the genomic and RNA expression levels of MCF-7 cells of different origins. Eight MCF-7 sublines collected from different sources were studied as well as 3 subclones isolated from one of the sublines by limit dilution. RESULTS: MCF-7 sublines showed important differences in copy number alteration (CNA) profiles. Overall numbers of events ranged from 28 to 41. Involved chromosomal regions varied greatly from a subline to another. A total of 62 chromosomal regions were affected by either gains or losses in the 11 sublines studied. We performed a phylogenetic analysis of CGH profiles using maximum parsimony in order to reconstruct the putative filiation of the 11 MCF-7 sublines. The phylogenetic tree obtained showed that the MCF-7 clade was characterized by a restricted set of 8 CNAs and that the most divergent subline occupied the position closest to the common ancestor. Expression profiles of 8 MCF-7 sublines were analyzed along with those of 19 unrelated breast cancer cell lines using home made cDNA arrays comprising 720 genes. Hierarchical clustering analysis of the expression data showed that 7/8 MCF-7 sublines were grouped forming a cluster while the remaining subline clustered with unrelated breast cancer cell lines. These data thus showed that MCF-7 sublines differed at both the genomic and phenotypic levels. CONCLUSIONS: The analysis of CGH profiles of the parent subline and its three subclones supported the heteroclonal nature of MCF-7 cells. This strongly suggested that the genetic plasticity of MCF-7 cells was related to their intrinsic capacity to generate clonal heterogeneity. We propose that MCF-7, and possibly the breast tumor it was derived from, evolved in a node like pattern, rather than according to a linear progression model. Due to their capacity to undergo rapid genetic changes MCF-7 cells could represent an interesting model for genetic evolution of breast tumors.

Breast Neoplasms↗

PubMed2003

Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease.

Although multiple myeloma (MM) is a unique entity, a marked heterogeneity is actually observed among the patients, which has been first related to immunoglobulin (Ig) types and light chain subtypes and more recently to chromosomal abnormalities. To further investigate this genetic heterogeneity, we analyzed gene expression profiles of 92 primary tumors according to their Ig types and light chain subtypes with DNA microarrays. Several clusters of genes involved in various biologic functions such as immune response, cell cycle control, signaling, apoptosis, cell adhesion, and structure significantly discriminated IgA- from IgG-MM. Genes associated with inhibition of differentiation and apoptosis induction were up-regulated while genes associated with immune response, cell cycle control, and apoptosis were down-regulated in IgA-MM. According to the expression of the 61 most discriminating genes, BJ-MM represented a separate subgroup that did not express either the genes characteristic of IgG-MM or those of IgA-MM at a high level. This suggests that transcriptional programs associated to the switch could be maintained up to plasma cell differentiation. Several genes whose products are known to stimulate bone remodeling discriminate between kappa- and lambda-MM. One of these genes, Mip-1alpha, was overexpressed in the kappa subgroup. In addition, we established a strong association (P =.0001) between kappa subgroup expressing high levels of Mip-1alpha and active myeloma bone disease. This study shows that DNA microarrays enable us to perform a molecular dissection of the bioclinical diversity of MM and provide new molecular tools to investigate the pathogenesis of malignant plasma cells.

Adult↗

PubMed2003

Breast cancer revisited using DNA array-based gene expression profiling.

Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. The resulting clinical heterogeneity makes current diagnostic and therapeutic strategies less than perfectly adapted to each patient. Pathological and clinical factors are insufficient to capture the complex cascade of events that drive the clinical behavior of tumors. High-throughput molecular technologies provide novel tools to tackle this complexity. In particular, DNA arrays allow the simultaneous and quantitative analysis of the mRNA expression levels of thousands of genes in a single assay. Potential applications are multiple in the cancer field and the first research results are promising; comprehensive gene expression profiles of breast tumors are providing insights into mammary oncogenesis and are revealing new tumor subgroups previously indistinguishable. Significant advances will be the identification of new diagnostic, prognostic and predictive biomarkers as well as the discovery of new potential therapeutic targets. This review presents recent applications of DNA arrays in breast cancer research and discusses some issues to address in the near future to allow the technology to reach its full potential.

Breast Neoplasms↗

PubMed2003

ParaDB: a tool for paralogy mapping in vertebrate genomes.

We present ParaDB (http://abi.marseille.inserm.fr/paradb/), a new database for large-scale paralogy studies in vertebrate genomes. We intended to collect all information (sequence, mapping and phylogenetic data) needed to map and detect new paralogous regions, previously defined as Paralogons. The AceDB database software was used to generate graphical objects and to organize data. General data were automatically collated from public sources (Ensembl, GadFly and RefSeq). ParaDB provides access to data derived from whole genome sequences (Homo sapiens, Mus musculus and Drosophila melanogaster): cDNA and protein sequences, positional information, bibliographical links. In addition, we provide BLAST results for each protein sequence, InParanoid orthologs and 'In-Paralogs' data, previously established paralogy data, and, to compare vertebrates and Drosophila, orthology data.

Animals↗

PubMed2003

A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene.

The 8p11-21 region is a frequent target of alterations in breast cancer and other carcinomas. We surveyed 34 breast tumor cell lines and 9 pancreatic cancer cell lines for alterations of this region by use of multicolor fluorescence in situ hybridization (M-FISH) and BAC-specific FISH. We describe a recurrent chromosome translocation breakpoint that targets the NRG1 gene on 8p12. NRG1 encodes growth factors of the neuregulin/heregulin-1 family that are ligands for tyrosine kinase receptors of the ERBB family. Breakpoints within the NRG1 gene were found in four of the breast tumor cell lines: ZR-75-1, in a dic(8;11); HCC1937, in a t(8;10)(p12;p12.1); SUM-52, in an hsr(8)(p12); UACC-812, in a t(3;8); and in two of the pancreatic cancer cell lines: PaTu I, in a der(8)t(4;8); and SUIT-2, in a del(8)(p). Mapping by two-color FISH showed that the breaks were scattered over 1.1 Mb within the NRG1 gene. It is already known that the MDA-MB-175 breast tumor cell line has a dic(8;11), with a breakpoint in NRG1 that fuses NRG1 to the DOC4 gene on 11q13. Thus, we have found a total of seven breakpoints, in two types of cancer cell lines, that target the NRG1 gene. This suggests that the NRG1 locus is a recurring target of translocations in carcinomas. PCR analysis of reverse-transcribed cell line RNAs revealed an extensive complexity of the NRG1 transcripts but failed to detect a consistent pattern of mRNA isoforms in the cell lines with NRG1 breakpoint.

Breast Neoplasms↗

PubMed2003

Serum levels of Hemorphin-7 peptides in patients with breast cancer.

BACKGROUND: Increased expression of cathepsin D (CD) and B (CB) is found in some cancers and correlates with the development of clinical metastases. It was suggested that these cathepsins could be used as prognostic markers, especially CD in breast cancer. Because serum level of Hemorphin-7 (H7) peptides could reflect CD activity, we have hypothesised that it could be used as a prognostic factor in breast cancer. METHODS: To verify this hypothesis, H7 serum levels from 62 breast cancer patients and 25 healthy controls were measured by ELISA. RESULTS: The mean serum concentration of H7 was 2.27+/-0.63 mumol/l in breast cancer patients in comparison with 4.09+/-1.05 mumol/l in controls (p=0.002). This reduced level of H7 in breast cancer could be due to the over-expression of CB, which exhibits strong interaction with H7 in vitro, with a ratio K(cat)/K(m) estimated at 18000 s(-1) M(-1). CONCLUSIONS: Because H7 serum levels did not correlate with other parameters including age, CA15-3 and ACE markers, it seems that they might be used as independent markers for the diagnosis of breast cancer.

Animals↗

PubMed2003

Chromosome arm 8p and cancer: a fragile hypothesis.

Chromosome arm 8p is one of the most frequently altered regions in human cancers. Several potential oncogenes and tumour suppressor genes have been identified but further investigations are needed to confirm which are bona fide oncogenic targets. In cancer cells, chromosome breaks may occur at fragile sites throughout the genome. Some fragile sites lie within genes that may have a role in cancer; the best example is FHIT at 3p14, which contains the fragile site FRA3B. We have found that chromosome breaks disrupt the NRG1 gene at 8p12 in breast and pancreatic cancers. We hypothesise that alteration of the NRG1 gene could occur through breakage at a non-common fragile site.

Acid Anhydride Hydrolases↗

PubMed2003

DNA arrays in clinical oncology: promises and challenges.

Cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. Current diagnostic and prognostic classifications, based on clinical and pathologic factors, are insufficient to reflect the whole clinical heterogeneity of tumors. Most current anticancer agents do not differentiate between cancerous and normal cells, leading sometimes to disastrous adverse effects. Recent advances in human genome research and high-throughput molecular technologies make it possible finally to tackle the molecular complexity of malignant tumors. With DNA array technology, mRNA expression levels of thousands of genes can be measured simultaneously in a single assay. Oncology is benefiting on multiple fronts. Gene expression profiles are revealing new biologically and clinically relevant tumor subclasses previously indistinguishable and are identifying new diagnostic and prognostic biomarkers as well as new potential therapeutic targets. Here, we review the technology and present clinical applications for which promising results have been obtained. Finally, we discuss issues that must be resolved in the near future to allow DNA arrays to translate into benefits for cancer patients.

Gene Expression Profiling↗

PubMed2003

[Tissue microarrays a powerful tool in transfer and quality control in oncology].

The progress in the knowledge of molecular genetics and the availability of high-throughput technologies offer the opportunity to identify new diagnostic and prognostic markers and new therapeutic targets in human cancer. The recently developed "tissue microarraysî (TMA) technology allows parallel molecular profiling of clinical samples. Using this technique and immunohistochemistry (IHC), fluorescence in situ hybridisation (FISH), or RNA in situ hybridisation (ISH), the pathologist is now able to perform unprecedented large-scale analyses. The advantages are significant: large number of cases assessed simultaneously for numerous markers, processing in identical conditions, reduced amount of archival tissues, excellent correlation with standard methods, reduction in cost and time. This article provides a short review of this technology, and points out several aspects of the TMA construction and its applications for clinical research.

Databases, Factual↗

PubMed2003

Characterization of Hodgkin's lymphoma-like undifferentiated carcinoma of the nasopharyngeal type as a particular UCNT subtype mimicking Hodgkin's lymphoma.

Undifferentiated carcinoma of the nasopharyngeal type (UCNT) that histologically mimics Hodgkin's lymphoma (HL) ("Hodgkin's lymphoma-like UCNT"--HL-like UCNT) is known as a diagnostic pitfall. Using immunohistochemistry, Western blot and cDNA array technology, we wanted to document its phenotypical and molecular characteristics. We report herein 5 cases of UCNT that morphologically mimic HL and 3 classical UCNT cases. We compared the expression profiles of a thousand selected genes in HL-like UCNT and in classical UCNT cases. No difference in the profile of EBV infection was noted between the HL-like UCNT and control cases. Significant differences were detected in the expression of genes involved in the matrix modelling, angiogenesis, apoptosis and regulation of the Th-2 interleukins. The eosinophil chemoattractant eotaxin was expressed in the stroma of HL-like UCNT, but not in the control cases. The eotaxin receptor CCR3 was expressed in both stromal and carcinoma cell populations of HL-like UCNT, this pattern being similar to the one observed in HL. These results show that UCNT morphologically resembling HL share also some specific phenotypical and molecular features with HL, and might deserve to be isolated as a particular UCNT subtype.

Apoptosis↗

PubMed2003

A further case of acute myelomonocytic leukemia with inv(8) chromosomal rearrangement and MOZ-NCOA2 gene fusion.

We report here the sixth case of acute monoblastic leukemia associated with the inv(8)(p11q13) pericentric inversion. As seen in the previous cases, the inv(8)(p11q13) molecular characterization showed that the alteration results in a MOZ-NCOA2 gene fusion. The presence of erythrophagocytosis is a distinctive morphologic feature that is observed in all patients with MOZ alteration. However, the relative young age of the 6 patients (median: 23.5 years) and same sex (female) are the common characteristics that are only observed in the inv(8)-positive leukemia subgroup. In addition, we tested whether the presence of FLT3 internal duplications (ITD) are frequently found in malignant hemopathies with 8p11-12 rearrangements. We did not find any FLT3 ITD in any of the studied cases.

Acetyltransferases↗

PubMed2003

[Inflammatory breast carcinoma: towards molecular characterization?].

Inflammatory Breast Carcinoma (IBC) is a rare but aggressive form of breast carcinoma. Characteristic clinical and pathological features are well documented. Pathological response to chemotherapy is currently the only identified prognostic factor. This high-grade tumor exhibits phenotypical features of an aggressive tumor: absence of hormonal receptors in 56 to 83% of cases, high proliferating index, p53 expressed in 30 to 69%, Immunohistochemistry (IHC) detection of HER2 over expression in 38 to 60%. Current work on IBC points out specific molecular mechanisms: adhesion molecules such as E-Cadherin, apomucin MUC1 and angiogenesis processes contribute to the IBC phenotype. So does a gene named WISP3. This gene has been recently cloned and sequenced. It has been shown to be lost in IBC and could control tumor growth, invasion, and angiogenesis. This paper summarizes current knowledge on IBC and describes a new basis for a molecular definition of IBC.

Breast Neoplasms↗

PubMed2003

[Small but high throughput: how "tissue-microarrays" became a favorite tool for pathologists and scientists].

Progress in the knowledge of molecular genetics and availability of high-throughput technologies offer the opportunity to identify new diagnostic and prognostic markers and new therapeutic targets in human cancer. The recently developed "tIssue microarrays" (TMA) technology allows parallel molecular profiling of clinical samples. Using this technique and immunohistochemistry (IHC), fluorescence in situ hybridisation (FISH), or RNA in situ hybridisation (ISH), the pathologist is now able to perform unprecedented large-scale analyses. The advantages are significant: large number of cases assessed simultaneously for numerous markers, processed in identical conditions, from reduced amount of archival tIssues, with an excellent correlation with standard methods, and a reduction in cost and time. This Article provides a short review of this technology, and points out several aspects of the TMA construction and its applications for clinical research.

Biomarkers↗