Download or read book Identification of Novel Tumor Suppressor Genes in Human Breast Cancer Using Nonsense Mediated MRNA Decay Inhibition NMDI Microarray Analysis written by and published by . This book was released on 2007 with total page 35 pages. Available in PDF, EPUB and Kindle. Book excerpt: This project sought to identify genes that harbor nonsense mutations in breast cancer cell lines that are commonly used as in vitro models in the study of breast cancer biology, with the ultimate aim of identifying novel tumor suppressor genes for sporadic breast cancer. We focused our efforts on the long arm chromosome 22 which is known to undergo LOH in primary breast tumors. Before the NMD-microarray strategy could be undertaken, we very thoroughly characterized chromosome 22q copy number and allelic imbalance in several breast cancer cell lines by integrating publicly available genetic data with empirical data derived from 317K single nucleotide polymorphism (SNP) arrays. MCF-7, T-47D, and MDA-MB-231 breast cancer-derived cell lines were selected for NMD-microarray analysis. Two different regimens for inhibiting NMD were then directly compared for their ability to specifically inhibit NMD while leaving wild-type transcripts unaffected. The improved second-generation NMD protocol was performed and we eagerly await the results of the Affymetrix GeneChip expression arrays so that interrogation of the expression data may begin.
Download or read book Identification of Novel Tumor Suppressor Genes for Breast Cancer written by and published by . This book was released on 2006 with total page 43 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chromosomal deletions are very common events in breast cancer. However, no TSGs have been identified from most of recurrent deletions and few identified TSGs do not account for the risk of majority of breast cancer. In additional to the classical TSGs, there are haplo-insufficient TSGs which defy the identification through mutation analysis and may be quite common. By using a new system to generate random chromosomal deletions, we identified a ~3Mbp deletion in mouse chromosome 3, which was associated with tumorigenesis. The expression of Fat4 in the deleted region was inactivated due to promoter methylation in the second allele of Fat4, and the re-expression of Fat4 suppressed the tumorigenecity, suggesting Fat4 as a strong candidate for breast tumor suppressor genes. We also found that Fat4 expression was lost in a high proportion of human breast cancers, some of which were attributed to Fat4 promoter methylation.
Download or read book Identification of Novel Tumor Suppressor Genes in Breast Cancer Using Gene Tapping Technique written by Leia M. Smith and published by . This book was released on 2001 with total page 20 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is a multi-step process resulting from a number of genetic changes in cells. The role of tumor suppressor genes in breast carcinogenesis, especially at the early stage, remains largely unknown. We hypothesize that during the transformation of a breast epithelial cell, loss of function of several yet unidentified genes (tumor suppressors) results in either a partially or fully transformed phenotype. The aim of this study is to identify% novel tumor suppressor genes involved in breast epithelial transformation using the gene-trapping technique. We used the polyA-trap retroviral vector pRET for infection into non-tumorigenic human mammary epithelial cells MCF 1 0A. We screened for clones where functional genes have been "trapped" by selection for G4 18-resistance. We essentially established a gene-trapped library of MCF 1 0A clones where expression of a single gene per clone is disrupted. We screened for transformed clones using the soft-agar cloning assay for anchorage independent growth. We isolated 25 transformed clones and identified the trapped genes in 5 clones by rapid amplification of cDNA ends (3 RACE). We identified 2 known genes and 2 novel genes as putative tumor suppressor genes. Further characterization of these genes will elucidate their role in the early transformation process in breast epithelial cells.
Download or read book Tumor Suppressor Genes written by Wafik S. El-Deiry and published by Springer Science & Business Media. This book was released on 2008-02-03 with total page 657 pages. Available in PDF, EPUB and Kindle. Book excerpt: It has become clear that tumors result from excessive cell proliferation and a corresponding reduction in cell death caused by the successive accumulation of mutations in key regulatory target genes over time. During the 1980s, a number of oncogenes were characterized, whereas from the 1990s to the present, the emp- sis has shifted to tumor suppressor genes (TSGs). It has become clear that oncogenes and TSGs function in the same pathways, providing positive and negative growth regulatory activities. The signaling pathways controlled by these genes involve virtually every process in cell biology, including nuclear events, cell cycle, cell death, cytoskeletal, cell membrane, angiogenesis, and cell adhesion effects. Mu- tions in tumor suppressor genes have been identified in familial cancer syndromes, and the same genes in many cases have been found to be mutationally inactivated in sporadically occurring cancers. In their normal state, TSGs control cancer development and progression, as well as contribute to the sensitivity of cancers to a variety of therapeutics. Understanding the classes of TSGs, the biochemical pa- ways they function in, and how they are regulated provides an essential lesson in cancer biology. We cannot hope to advance our current knowledge and to develop new and more effective therapies without understanding the relevant pathways and how they influence the present approaches to therapy. Moreover, it is important to be able to access not only the powerful tools now available to discover these genes, but also their links to cell biology and growth control.
Download or read book Tumor Suppressor Genes written by Katherine R. Polinsky and published by Nova Publishers. This book was released on 2007 with total page 332 pages. Available in PDF, EPUB and Kindle. Book excerpt: A tumour suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor. Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. This book presents new and important research from throughout the world.
Download or read book Tumor Suppressor Genes written by Wafik S. El-Deiry and published by Springer Science & Business Media. This book was released on 2008-02-03 with total page 502 pages. Available in PDF, EPUB and Kindle. Book excerpt: It has become clear that tumors arise from excessive cell proliferation and a c- responding reduction in cell death. Tumors result from the successive accumulation of mutations in key regulatory target genes over time. During the 1980s, a number of oncogenes were characterized, whereas from the 1990s to the present, the emphasis shifted to tumor suppressor genes (TSGs). It has become clear that oncogenes and tumor suppressor genes function in the same pathways, providing positive and ne- tive growth regulatory activities. The signaling pathways controlled by these genes involve virtually every process in cell biology, including nuclear events, cell cycle, cell death, cytoskeletal, cell membrane, angiogenesis, and cell adhesion effects. Tumor suppressor genes are mutated in hereditary cancer syndromes, as well as somatically in nonhereditary cancers. In their normal state, TSGs control cancer development and p- gression, as well as contribute to the sensitivity of cancers to a variety of therapeutics. Understanding the classes of TSGs, the biochemical pathways they function in, and how they are regulated provides an essential lesson in cancer biology. We cannot hope to advance our current knowledge and to develop new and more effective therapies without understanding the relevant pathways and how they influence the present approaches to therapy. Moreover, it is important to be able to access the powerful tools now available to discover these genes, as well as their links to cell biology and growth control.
Download or read book Mechanisms Underlying the Pharmacologic Reversal of Genetic and Epigenetic Components of Tumor Suppressor Gene Silencing in Human Breast Cancer written by and published by . This book was released on 2006 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: In women, tumors of the breast remain the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths. One of the hallmarks of carcinogenesis is the abnormal silencing of tumor supprsssor genes by both genetic and epigenetic alterations, leading to defects in cell-cycle control, DNA repair, apoptosis and cell adhesion. This dissertation focuses on the elucidation of the genetic and epigenetic mechanisms associated with tumor suppressor gene silencing in human epithelial breast tumor cells, and the development of pharmacologic strategies aimed at reversing these types of repression through gene therapy and chromatin remodeling. Desmocollin 3 (DSC3) and MASPIN are anti-metastatic tumor suppressor genes that are silenced in a large percentage of breast tumors via aberrant DNA hypermethylation and histone hypoacetylation of their promoters. DSC3 and MASPIN are also p53-target genes, requiring its transcriptional activation to promote normal expression levels, yet a significant fraction of breast tumor cell lines express mutant forms of p53. Adenoviral-mediated re-introduction of wild type (wt) p53 into mutant p53-expressing breast tumor cells resulted in significant up-regulation of DSC3 and MASPIN expression, although not to the levels seen in normal breast epithelial cells. Mechanistically, the addition of wt p53 to these tumor cells resulted in increased histone acetylation and enhanced chromatin accessibility of the DSC3 and MASPIN promoters, despite continued cytosine hypermethylation. Pre-treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) prior to wt p53 addition produced synergistic reactivation of both DSC3 and MASPIN in breast cancer cells, approaching their levelsin normal mammary cells. However, 5-aza-CdR did not significantly reduce DNA methylation in many cases as originally theorized. Therefore, follow-up studies focused on the identification of alternative, novel mechanisms of 5-aza-CdR-mediated induction of epigenetically silenced genes, finding that it consistently reduced transcriptionally repressive histone H3 lysine 9 (K9) methylation levels in the promoter regions of both DSC3 and MASPIN in breast tumor cells, by mediating global decreases in the histone H3 K9 methyltransferase, G9A. In summary, these results clearly show that cancer treatments targeting both genetic and epigenetic facets of gene regulation may be a useful strategy towards the therapeutic transcriptional reprogramming of cancer cells.
Download or read book Tumor Suppressor Genes in Human Cancer written by David E. Fisher and published by Springer Science & Business Media. This book was released on 2000-10-26 with total page 441 pages. Available in PDF, EPUB and Kindle. Book excerpt: David Fisher, MD, PhD, and an authoritative panel of academic, cutting-edge researchers review and summarize the current state of the field. Describing the broad roles of tumor suppressors from a perspective based in molecular biology and genetics, the authors detail the major suppressors and the pathways they regulate, including cell cycle progression, stress responses, apoptosis, and responses to DNA damage. Leading-edge and forward-looking, Tumor Suppressor Genes in Human Cancer illuminates what is currently known of tumor suppressor genes and their regulation, work that is already beginning to revolutionize cancer target elucidation, drug discovery, and treatment design.
Download or read book Identification of Tumor Suppressor Genes in Breast Cancer by International Mutagenesis and Functional Inactivation written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer is the most common malignancy in Western women, affecting up to one in 10 women during their lifetime and approximately 40,000 women dying from the disease each year in the U.S. Tumor genetic profiling through such methods as loss of heterozygosity (LOM) screening, comparative genomic hybridization (CGll), and cDNA microarrays all point to the same conclusion that a number of genetic changes are responsible for the malignant phenotype. For example, genes involved in breast cancer progression include amplification of oncogenes such as MYC, ERBB2, CCNDl and mutation of tumor suppressor genes TP53 and CHDlL. In case of hereditary breast cancer, germline mutations of tumor suppressor genes PTEN on chromosome 10q23.3, ATM on chromosome 1 lq22-q23, BRCAl on chromosome l7q21, and BRCA2 on chromosome l3ql2.3 were also shown to involve in the tumor progression 2. These data represent a significant advance in our understanding of molecular genetics of breast cancer. However, breast cancer is a heterogeneous disease that entails complex genetic alterations in which tumor suppressor genes, oncogenes, and modulator genes were mutated. Multi step genetic alterations transform normal mammary epithelial cells via the steps of hypeiplasia, premalignant change, in situ carcinoma, invasion, and metastases. Genome-wide searching for the alterations and the elucidation of molecular events involved in these steps is the main focus for new strategies targeted at diagnosis, prevention and treatment.
Download or read book Suppressor Genes in Breast Cancer written by and published by . This book was released on 1999 with total page 24 pages. Available in PDF, EPUB and Kindle. Book excerpt: Several tumor suppressor genes (TSGs) have been cloned and found to be mutated in a variety of cancers, including breast cancer. However, few breast cancer specific TSGs are known. The purposes of this proposal are to: (1) generate cDNA expression libraries from reduction mammoplasties, (2) use a novel functional assay to clone new TSGs specific to human breast cancer, and (3) identify their characteristics, regulation and function. We are utilizing the tetracycline (tet) regulable system. We have constructed a cDNA library from normal human breast epithelia and cloned this cDNA library into a vector that is negatively regulated by tat repressor (tetR) and simultaneously expresses the enhanced green fluorescent protein. These vectors were then co-transfected into LCC6, MDA231, and MCF-7 cells that have the capability to express tetR. Upon withdrawal of tet, the repressed expression of the cDNA of interest is released, and the cDNA is expressed. Using a novel dye retained in nonproliferating cells, we were able to identify growth inhibited clones which were then sorted by Flow Cytometry. This functional screen has provided the basis for identifying TSGs that are expressed in the growth inhibited cells. Using PCR, we have obtained and sequenced two insert sequences. One is a putative TSG on chromosome #9 (725 bp) but the other sequence is vector DNA.
Download or read book Identification and Cloning a Novel Tumor Suppressor Gene in Breast Cancer written by and published by . This book was released on 1998 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: On the basis of an extensive body of cytogenetic literature as well as molecular evidence from our laboratory, we hypothesize that a tumor suppressor gene is located on the long arm of Human Chromosome 7 at the q3 1.1 band. Furthermore, we propose that inactivation of this tumor suppressor gene plays a role in the development of breast cancer. The long term objectives of the study are to identify and clone the tumor suppressor gene and to determine its function. The objectives for the requested funding period are to provide functional evidence for the existence of this tumor suppressor gene in breast cancer using microcell fusion and to clone the DNA fragment containing the putative tumor suppressor gene using a novel approach based on the introduction of Yeast Artificial Chromosomes (YACs) into breast cancer cells. This novel approach will facilitate the cloning of putative tumor suppressor genes closing the technical gaps that exist between the identification of deleted regions of genome containing putative tumor suppressor genes and the actual cloning of DNA fragments containing the candidate genes.
Download or read book Identification of Transcriptionally Deregulated Genes in Breast Cancer written by Minh Dong To and published by . This book was released on 1998 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Identification of Metastasis Suppressor Signaling Pathways in Breast Cancer written by Miao Sun and published by . This book was released on 2013 with total page 146 pages. Available in PDF, EPUB and Kindle. Book excerpt: Elucidating targets of physiological metastasis suppressors can highlight key signaling pathways leading to tumor invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP), I developed an integrated approach based on statistical analysis of tumor gene expression data combined with experimental validation. In the first part of the thesis, I utilized this approach to identify and validate two novel signaling pathways targeted by RKIP that promote HMGA2-driven metastasis in human breast cancer. RKIP induces and HMGA2 inhibits expression of miR-200b, and miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2 ) via down-regulation of HMGA2, but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. The RKIP/LOX/SDC2 signature is prognostic for metastasis-free survival in ER-negative breast cancer patients. To further identify critical downstream targets of HMGA2 in human breast cancer, I did gene and microRNA expression array analyses of human breast cancer cells with depleted HMGA2 expression. In the second part of the thesis, I show that TET1 and HOXA9 are important effectors of HMGA2. Depletion of HMGA2 induces TET1 expression. TET1 binds and demethylates its own promoter as well as the promoters of HOXA genes, stimulating TET1 and HOXA gene expression. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts, and a gene signature based upon HMGA2, TET1, and HOXA9 expression is prognostic for overall survival in breast cancer patients. These results implicate the HMGA2-TET1-HOXA9 signaling pathway in the epigenetic regulation of breast cancer and highlight the importance of targeting methylation as a potential therapeutic strategy.
Download or read book Identification of Novel Candidate Tumor Suppressor Genes Using C Elegans as a Model written by and published by . This book was released on 1999 with total page 7 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular genetic analysis of the model organism Caenorhabditis elegans was used to identify and study mechanisms of action of negative regulators of tyrosine kinase/RAS mediated signal transduction that are candidate tumor suppressors. A homolog of the proto oncogene cbl, SLI- 1, inhibits Ras activation by the epidermal growth factor receptor homolog LET-23. Three functional domains of SLI-1 have been identified. The ARK-i protein kinase was discovered and shown to inhibit signaling by LET-23. New screens for additional negative regulators have identified at several genes that will be molecularly cloned.
Download or read book Zack Badanna 1933 written by and published by . This book was released on with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The folder may include clippings, announcements, small exhibition catalogs, and other ephemeral items.
Download or read book Analysis of a Novel Breast Cancer Growth Suppressor Gene on Chromosome 17 written by and published by . This book was released on 1995 with total page 13 pages. Available in PDF, EPUB and Kindle. Book excerpt: Understanding the genetic basis of cancer will greatly improve our ability to develop more effective therapies. One family of genes involved in cancer is the tumor suppressor genes. We have functional evidence for a new breast cancer suppressor gene on chromosome 17. Transfer of a normal human chromosome 17 results in growth arrest of the MCF7 breast cancer cell line. We are using two approaches to localize the region containing this gene. The first involves the transfer of chromosome 17s containing specific deletions into MCF7 cells followed by our growth arrest assay to determine whether that chromosome contains the suppressor gene. We have determined that the gene lies on chromosome 17q and are now further localizing this gene. In parallel, we are studying loss of heterozygosity (or LOH, which is an indirect indicator of the presence of a suppressor gene) in breast tumors and have identified at least three candidate LOH regions on chromosome 17. Future studies will involve physical mapping of the region containing the suppressor gene, and we provide evidence for our ability to develop region-specific markers. We have also undertaken feasibility studies to determine whether YACs can be used in the MCF7 growth arrest assay.
Download or read book Tumor Suppressor Genes written by Wafik S. El-Deiry and published by Humana PressInc. This book was released on 2003-04-21 with total page 657 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tumor Suppressor Genes provides a timely foundation for understanding cancer. It provides critical information to rapidly gain appreciation of important tumor suppressor genes in human cancer as well as modern methods for their discovery, analysis, and clinical application. It covers all the known tumor suppressor pathways and provides key information on the road to their discovery and use in cancer therapy. Volume I of this text, educates the reader on the relevance of known tumor suppressor genes (TSGs) and the relevance of the biochemical pathways they regulate to human cancer. The reader has an opportunity in volume I to access state-of-the-art protocols that have been successful in the identification of TSGs in the past and which can be applied to isolate novel TSGs. With a novel TSG at hand, the reader has an opportunity in volume II to explore the cell biology and biochemical function of the encoded protein, as well as its physiological role in-vivo. Also contained in volume II, strategies for the use of information on TSGs to develop diagnostic and therapeutic strategies for cancer are presented. This two-volume text brings together the world's most expert researchers in the identification and characterization of tumor suppressor genes.
