Download or read book A Mouse Model for the Cloning of a Tumor Suppressor Gene Mutated in Sporadic Breast Cancer written by and published by . This book was released on 1997 with total page 32 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report serves as the annual report for the period beginning July 1, 1996 for the project entitled "A Mouse Model for the Cloning of a Tumor Suppressor Gene Mutated in Sporadic Breast Cancer. This report states the experimental progress made and proposes a modification of an original specific aim. This modification serves to facilitate the speed of the research and substantially reduces the numbers of mice to be used in the study.
Download or read book Mouse Models of Human Cancer written by Eric C. Holland and published by John Wiley & Sons. This book was released on 2004-08-27 with total page 504 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mice have become the species of choice for modeling the complex interactions between tumor cells and the host environment. Mouse genetics are easily manipulated, and a growing array of technology exists for this purpose. Mouse models allow investigators to better understand causal relationships between specific genetic alterations and tumors, utilize new imaging techniques, and test novel therapies. Recent developments along these lines show great promise for the development of new anti-cancer treatments. Mouse Models of Human Cancer provides researchers and students with a complete resource on the subject, systematically presenting the principles, methodologies, applications, and challenges associated with this exciting field. Offering a survey of the latest research and a description of future areas of interest, this text: Presents real experimental data Describes organ site-specific mouse models Clearly identifies suitable models for further drug testing Critically analyzes current methodologies and their limitations Features numerous recognizable expert contributors Lists key Web sites, reagents, and companies From mouse handling and genetic engineering to preclinical trials, Mouse Models of Human Cancer is a comprehensive guide to using these models and relating them to human disease. Its uniform presentation describes organ-specific models in clinical, imaging, and molecular terms, and lays out the relevant genetics, experimental approaches, histological comparisons with human disease, and conclusions. Combining stellar chapter authors, rich illustrations, and clear, up-to-date coverage, Mouse Models of Human Cancer is an invaluable resource for advanced students and cutting-edge researchers.
Download or read book Cloning of Tumor Suppressor Genes in Breast Cancer written by and published by . This book was released on 2003 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer arises through the accumulation of genetic alterations that affect two classes of genes, oncogenes and tumor suppressor genes. These genes must be identified for several reasons. Characterization of the genes that drive carcinogenesis will facilitate a better understanding of cancer development. As part of this big picture, we have studied tumor suppressor genes involved in breast cancer. A tumor suppressor candidate, DBC2 was analyzed. DBC2 is a structurally new gene and its function remains to be studied. DBC2 is composed of a BAS domain, protein-protein interacting domains, and DNA binding domain. DBC2 expression is extinguished in more than half of breast tumors we tested. Methylation analysis of tumor cells revealed hypermethylation of the CpG islands in the DBC2 promoter region. Additionally, we have discovered somatic mutations of DBC2 in breast cancer. These mutations are accompanied by LOB. When DBC2 expression was induced in tumor cells, the cell growth was hindered. In contrast naturally occurring mutants did not suppress growth of the tumor cells. Our findings suggest that DBC2 is the target of mutations at 8p22.
Download or read book Genetically Engineered Mice for Cancer Research written by Jeffrey E. Green and published by Springer Science & Business Media. This book was released on 2011-12-09 with total page 639 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genetically-engineered mouse models for cancer research have become invaluable tools for studying cancer biology and evaluating novel therapeutic approaches. This volume focuses on state-of-the-art methods for generating, analyzing and validating such models for studying aspects of human cancer biology. Additionally, these models are emerging as important pre-clinical systems in which to test cancer prevention and therapeutic strategies in order to select compounds for testing in clinical trials.
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 Evolution in Mammary Cancer written by Maryknoll Linscott and published by . This book was released on 2024 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer, a highly heterogeneous disease, is a product of dynamic variation and selection of mutant clones. The continuous evolution of breast tumor cells has important implications for patient outcomes due to its impacts on treatment response, resistance, and relapse. While a wealth of studies has been conducted on the genetic and epigenetic aberrations that confer a fitness advantage to tumor cells, the sources of selective pressure remain to be understood. Using various clinically relevant mouse models of breast cancer, this dissertation investigates whether and how three factors, which are not mutually exclusive, drive the selection of genetically distinct breast tumor clones: the source of oncogenic signaling (namely, the specific oncogene sustaining an activating mutation); the context of oncogenic signaling (namely, the reproductive history of the mammary cell undergoing transformation); and the strength of oncogenic signaling (as determined by oncogene expression levels). In the first set of experiments directed at modeling breast cancer as a multistage disease, we evaluated how clinically relevant oncogenes Myc and PIK3CA shape the progression of premalignant clones to mammary tumors. By using a well-studied carcinogen, DMBA (7,12-Dimethylbenz[a]anthracene), stereotypical Hras, Kras, and Nras mutations (exons 12, 13, and 61) were randomly introduced in our mouse models. Mice were engineered for mammary-specific, doxycycline (Dox)-inducible expression of either Myc (iMyc mice) or PIK3CAH1047R (iPIK mice). However, despite the introduction of possibly innumerable mutations in the entire organism, only mammary tumors were observed in our studies. These tumors only arose when Myc and PIK3CAH1047R were individually expressed in the mammary glands of our mouse models, which signifies that the tumors occurred in a stepwise fashion. Notably, a different set of Ras-initiated cells comprised the dominant population in Myc- versus PIK3CAH1047R-driven tumors, which suggests that each oncogene prefers to cooperate with specific mutant Ras family member(s). We discovered that while Myc selects for the outgrowth of Nrasmut and Krasmut tumors, PIK3CAH1047R only selects for the outgrowth of Krasmut tumors. Based on our findings, we propose that cooperating oncogenes provide selective pressure for genetically distinct Ras-initiated premalignant clones. In a second set of experiments, we evaluated how parity impacts the progression of premalignant clones. We first tested whether parity blocks tumorigenesis by modifying our first set of experiments to include one or two rounds of parity after DMBA initiation and before inducing the expression of an oncogenic transgene. Despite the known protective effects of pregnancy against breast cancer, our parity protocols did not block tumorigenesis, regardless of cooperating oncogene (Myc vs. PIK3CAH1047R) and the number (one vs. two) and timing (peri-pubertal vs. adulthood) of pregnancies. However, parity did impact which clones progressed to malignancy. In both Myc- and PIK3CAH1047R-expressing models, the prevalence of Krasmut tumors was decreased in the context of parity, which implies that parity exerted selective pressure against the progression of Krasmut clones. Moreover, this selective pressure appears stronger as the number of pregnancies increases regardless of the cooperating oncogene and timing of pregnancy, as demonstrated by the decreased prevalence of Krasmut tumors. Lastly, pubertal parity revealed a slightly stronger selection against the Krasmut premalignant clone in PIK3CAH1047R-expressing models compared to adult parity. Thus, parity can exert contextual selection against specific Ras-initiated premalignant clones. In a third and final set of experiments aimed at targeting "undruggable" Myc-driven tumorigenesis, we discovered that Myc selects for a threshold level of PI3K signaling activation. While previous studies show that Myc cooperates with oncogenic Ras, targeted therapies against Ras remain limited to G12C Kras mutants, which is rare in human breast cancer. Hypothesizing that Myc/Ras cooperation involves the activation of a specific downstream Ras effector pathway, namely the phosphoinositide 3-kinase (PI3K) pathway, we generated a mouse model that expresses both iPIK transgene and constitutive, mammary-specific Myc transgene (cMyc). By inducing various levels of PIK3CAH1047R expression, we demonstrated that Myc requires a minimum level of PI3K pathway activation to generate mammary tumors reliably with decreased latency and increased multiplicity. These tumors also lack stereotypical Ras mutations, which implies that PI3K pathway activation relieved the selective pressure to select for Rasmut Myc-driven tumors. In addition, PIK3CAH1047R expression was reactivated by gene-switch mutations in Myc-expressing relapse tumors, further reinforcing a strong selective pressure for PI3K pathway activation.
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 Molecular Biology of the Cell written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Genome Stability written by Igor Kovalchuk and published by Academic Press. This book was released on 2021-07-17 with total page 762 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genome Stability: From Virus to Human Application, Second Edition, a volume in the Translational Epigenetics series, explores how various species maintain genome stability and genome diversification in response to environmental factors. Here, across thirty-eight chapters, leading researchers provide a deep analysis of genome stability in DNA/RNA viruses, prokaryotes, single cell eukaryotes, lower multicellular eukaryotes, and mammals, examining how epigenetic factors contribute to genome stability and how these species pass memories of encounters to progeny. Topics also include major DNA repair mechanisms, the role of chromatin in genome stability, human diseases associated with genome instability, and genome stability in response to aging. This second edition has been fully revised to address evolving research trends, including CRISPRs/Cas9 genome editing; conventional versus transgenic genome instability; breeding and genetic diseases associated with abnormal DNA repair; RNA and extrachromosomal DNA; cloning, stem cells, and embryo development; programmed genome instability; and conserved and divergent features of repair. This volume is an essential resource for geneticists, epigeneticists, and molecular biologists who are looking to gain a deeper understanding of this rapidly expanding field, and can also be of great use to advanced students who are looking to gain additional expertise in genome stability. A deep analysis of genome stability research from various kingdoms, including epigenetics and transgenerational effects Provides comprehensive coverage of mechanisms utilized by different organisms to maintain genomic stability Contains applications of genome instability research and outcomes for human disease Features all-new chapters on evolving areas of genome stability research, including CRISPRs/Cas9 genome editing, RNA and extrachromosomal DNA, programmed genome instability, and conserved and divergent features of repair
Download or read book Clinical Gynecology written by Eric J. Bieber and published by Cambridge University Press. This book was released on 2015-04-23 with total page 1127 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written with the busy practice in mind, this book delivers clinically focused, evidence-based gynecology guidance in a quick-reference format. It explores etiology, screening, tests, diagnosis, and treatment for a full range of gynecologic health issues. The coverage includes the full range of gynecologic malignancies, reproductive endocrinology and infertility, infectious diseases, urogynecologic problems, gynecologic concerns in children and adolescents, and surgical interventions including minimally invasive surgical procedures. Information is easy to find and absorb owing to the extensive use of full-color diagrams, algorithms, and illustrations. The new edition has been expanded to include aspects of gynecology important in international and resource-poor settings.
Download or read book The P53 Deficient Mouse as a Breast Cancer Model written by Lawrence Donehower and published by . This book was released on 1997 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: The p53 tumor suppressor gene is mutated in about half of all human cancers and in roughly 30-40% of breast cancers. In order to better understand the role of p53 mutation and loss in breast cancer progression, we have developed a mouse model which is genetically programmed to develop mammary cancer in the presence and absence of p53. By comparison of the mammary tumorigenesis process between the p53 positive and p53 negative animals we hope to obtain further insights into the mechanisms by which loss of p53 accelerates tumor progression. In the first three years of this grant we have shown that in the absence of p53 mammary tumors arise sooner and grow faster than mammary tumors with intact p53. We have also shown that tumors without p53 have higher levels of chromosomal instability and higher rates of cell proliferation than tumors with p53. Rates of apoptosis (programmed cell death) and angiogenesis (tumor vascularization) were not significantly different between p53 positive and negative tumors. We have examined the role of the p53-inducible cyclin-dependent kinase inhibitor p21 in mammary tumor progression and have shown that reduction of p21 accelerates tumor cell proliferation rates. Thus, the model is useful in elucidating the role of p53 loss in tumorigenesis and indicates that p53 has multiple roles in prevention of tumor formation and progression.
Download or read book Transgenic Repository for Breast Cancer Research written by and published by . This book was released on 1995 with total page 20 pages. Available in PDF, EPUB and Kindle. Book excerpt: The overall goal of this project is to develop and maintain a resource of mouse models for breast cancer research. Eleven induced mutant strains have been identified nd accepted into The Jacks on Laboratory (TJL) Induced Mutant Resource (IMR) repositor or breast cancer research models. The importation process frees mice of infectious pathogens. Embryos are cryopreserved. Correct nomenclature has been assigned, efficient breeding strategies have been developed, and typing protocols are being modified for optimal efficiency and accuracy. Strain availability is being announced in several media, including the IMR strain list accessed through TJL's WWW home page. A principal aim of this project is to transfer relevant mutations to defined genetic backgrounds. Many of these mutations were generated on mixed genetic backgrounds, which limits their usefulness for most genetic studies. After consultation with Associated Board members and other experts in the field, we have decided that transgenes arriving in mixed genetic backgrounds be transferred to the FVB inbred background. In addition, the transfer of tumor suppressor genes to backgrounds with defined susceptibility to mammary carcinogenesis may convey specific experimental advantages. The Trp53 and Rbl targeted mutations are being transferred to the BALB/cJ and C3H/OuJ inbred strains.
Download or read book Multistage Breast Carcinogenesis Modeling Using Transgenic Mice written by Shuo Li and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely-used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated initiated mammary epithelial cells (iMECs) by introducing a stereotyped HRasQ61L driver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired long-lived iMEC clones that eluded detection by histology and persisted in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas (DMBA/iWnt tumors), while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.Since DMBA/iWnt tumors recurrently acquired somatic HRasQ61L mutations, we hypothesized that their maintenance and growth require sustained activation of an HRas-regulated signaling pathway. Taking a pharmacologic approach, we found that DMBA/iWnt tumors show a marked sensitivity to the MEK inhibitor drug trametinib, suggesting dependence on Mitogen-Activated Protein Kinase (MAPK) pathway activation. However, while DMBA/iWnt tumors invariably responded to trametinib, these responses were neither complete nor durable. Instead, trametinib-resistant relapses reproducibly emerged at each site of residual disease in a quasi-synchronous manner after approximately 3 weeks of treatment. Treatment of DMBA/iWnt tumors with a structurally distinct MEK inhibitor, Cobimetinib, precisely reproduced this pattern of response and relapse, indicating trametinib acts on target to achieve transient tumor regression. In preclinical studies, resistance to MEK inhibitor treatment sometimes involves selection for Ras-mutant subclones bearing genetic changes that result in an increased mutant allele fraction (MAF). Concordantly, outgrowth of trametinib-resistant DMBA/iWnt tumors selected for tumors bearing an increased HRasQ61L MAF. Together, these data strongly support the concept that HRasQ61L acts through the downstream MAPK pathway not only to drive growth of DMBA/iWnt tumors, but also to drive trametinib-resistant relapse.In human breast cancer, some treatments that yield only transient responses when directed against advanced disease can prevent cancer onset or yield cures when applied at an earlier disease stage. Accordingly, we tested whether trametinib treatment was capable of eliminating subclinical DMBA/iWnt tumors or newly-generated iMECs. Short-term trametinib treatment administered prior to outgrowth of DMBA/iWnt tumors failed to reduce tumor multiplicity or delay onset. Although chronic trametinib treatment delayed tumor onset, tumor multiplicity was not reduced, again indicating a failure to eradicate HRasQ61L mutant iMECs. Finally, we tested whether adaptive therapy schedules incorporating trametinib treatment holidays would delay outgrowth of trametinib-resistant disease. While repeated rounds of intermittent trametinib treatment continued to yield partial responses, overall tumor burden increased steadily over time such that adaptive therapy schedules offered no advantage over chronic therapy. Overall, DMBA-induced iMECs model a common clinical scenario in breast cancer patients, in whom long-lived, treatment-refractory, subclinical disease often persists as an enduring source of relapse.Since DMBA/iWnt tumors show a stereotyped pattern of response and resistance to MEK inhibition, we sought to determine whether this phenotype is a specific feature of the DMBA-induced HRasQ61L genotype. To shift cooperating mutations away from HRasQ61L, we modified our multistage modeling strategy by using N-ethyl-N-nitrosourea (ENU) exposure for the initiation step, in place of DMBA. Unlike DMBA/iWnt tumors, ENU/iWnt mammary tumors varied in genotype: most tumors acquired an activating mutation in either Braf or HRas, whereas still other tumors lacked a mutation in either of these genes (i.e, they were Ras/Raf wild-type; Ras/Rafwt). ENU/iWnt tumors bearing distinct genotypes (Brafmut vs. HRasmut vs. Raf/Raswt) showed indistinguishable onset, growth, and histological features under normal physiological conditions. However, when challenged with MAPK inhibitor drugs, clinical outcomes sometimes varied by tumor genotype in important ways. Established ENU/iWnt tumors, including Brafmut tumors, failed to respond to vemurafenib, a potent inhibitor of activated Braf mutants. By contrast, established ENU/iWnt tumors responded dramatically to trametinib, regardless of tumor genotype. While all ENU/iWnt tumor genotypes were capable of yielding trametinib-resistant disease, HRasmut tumors showed the highest incidence of relapse. Intriguingly, beginning chronic trametinib treatment prior to mammary tumor onset not only delayed tumorigenesis and extended survival, but also selectively prevented outgrowth of Brafmut tumors. Notably, Brafmut iMECs were suppressed but not eliminated by trametinib treatment, since Brafmut tumors emerged shortly after trametinib withdrawal. Together, our findings suggest that tumor genotype may impact treatment outcome more strongly when drugs are employed against early-stage disease.
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 Hunting for Novel X Linked Breast Cancer Suppressor Genes in Mouse and Human written by and published by . This book was released on 2007 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: A priori X-linked tumor suppressor genes would be of great interest as one allele of these genes might be silenced due to X-chromosome inactivation. The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression regardless of the status of HER-2 amplification. In toto the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
Download or read book Genetic Basis for Carcinogenesis written by Takamatsu no Miya Hi Gan Kenkyū Kikin. International Symposium and published by Taylor & Francis Group. This book was released on 1990 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume brings together the latest studies on various aspects of molecular oncology. It emphasizes the current view that oncogenes and suppressor genes need to be discussed in the same context.
Download or read book Cumulated Index Medicus written by and published by . This book was released on 2000 with total page 1844 pages. Available in PDF, EPUB and Kindle. Book excerpt:
