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 Tumor Models in Cancer Research written by Beverly A. Teicher and published by Springer Science & Business Media. This book was released on 2001-11-07 with total page 745 pages. Available in PDF, EPUB and Kindle. Book excerpt: Beverly A. Teicher and a panel of leading experts comprehensively describe for the first time in many years the state-of-the-art in animal tumor model research. The wide array of models detailed form the basis for the selection of compounds and treatments that go into clinical testing of patients, and include syngeneic models, human tumor xenograft models, orthotopic models, metastatic models, transgenic models, and gene knockout models. Synthesizing many years experience with all the major in vivo models currently available for the study of malignant disease, Tumor Models in Cancer Research provides preclinical and clinical cancer researchers alike with a comprehensive guide to the selection of these models, their effective use, and the optimal interpretation of their results.
Download or read book Mouse Mammary Cancer Models Mechanisms and Markers written by and published by . This book was released on 2002 with total page 23 pages. Available in PDF, EPUB and Kindle. Book excerpt: We have generated and characterized several mouse models to better understand the role of breast cancer associated genes in an experimentally manipulable context. We have focused on the role of p53 and p53 target genes and their role in promoting mammary cancer. Recent emphasis has been placed on the Wild type p53-Induced Phosphatase (Wip1), also known as Ppm1D. This gene has recently been demonstrated to be an oncogene in vitro and to be specifically amplified in more than 15% of human breast cancers. To study the role of Wip1 in mammalian development, physiology, and cell cycle control, we generated knockout mice that are deficient in Wip1. Wip1-deficient mice exhibit multiple developmental defects and their cells show defects in cell cycle progression. We have confirmed that Wip1 is radiation-induced p53 target gene and we have identified three novel potential Wip1 interacting proteins.
Download or read book Development of Spontaneous Mammary Tumors in BALB c p53 Mice Detection of Early Genetic Alterations and the Mapping of BALB c Susceptibility Genes written by and published by . This book was released on 2002 with total page 19 pages. Available in PDF, EPUB and Kindle. Book excerpt: The TP53 tumor suppressor gene is defective in the majority of sporadic breast cancers, and breast cancer is the most frequent tumor type in women with Li-Fraumeni syndrome who inherit germline mutations in TP53. This suggests that p53 is fundamental to the growth regulation and prevention of tumor formation in mammary epithelial cells. Our laboratory has backcrossed the p53-null allele in mice onto the BALB/c genetic background. We have recently described the occurrence of mammary tumors in 55% of female BALB/c-p53+/- mice with a latency of 8-14 months(1). This is in contrast to C57BL/6- and 129/Sv-p53+/- mice, which rarely develop mammary tumors (2), suggesting that the BALB/c-p53+/- mice serve as a unique model for Li-Fraumeni syndrome (LFS). The experiments proposed in this fellowship are designed to characterize the BALB/c- p53+/- mouse model of breast cancer with respect to the progression of the glands towards tumor formation, and with respect to genetic contributions towards tumor susceptibility which are particular to this strain of mouse.
Download or read book Mapping Genetic Modifiers of Mammary Tumor Susceptibility in BALB c Trp53 Mice written by D. J. Jerry and published by . This book was released on 2002 with total page 10 pages. Available in PDF, EPUB and Kindle. Book excerpt: The TP53 tumor suppressor gene is defective in the majority of sporadic breast cancers. Breast cancer is also the most frequent tumor type in women with Li-Fraumeni syndrome who inherit germline mutations in TP53. This suggests that p53 is fundamental to the growth regulation and prevention of tumors in the mammary epithelium. However, the incidence of mammary tumors in p53-deficient mice varies greatly among strains. We have undertaken the genetic mapping of modifiers of susceptibility by performing genetic crosses between mammary tumor-susceptible BALB/c-Trp53+/- mice and -resistant C57BL/6-Trp53+/- mice. Mammary tumor susceptibility was shown to segregate as a partially dominant trait with recessive-acting modifiers also detected.
Download or read book The Development of BRCA2 Deficient Mice written by and published by . This book was released on 2002 with total page 40 pages. Available in PDF, EPUB and Kindle. Book excerpt: Women who inherit a BRCA1 or BRCA2 mutation have an 80-90% chance of developing breast cancer. Gene targeting techniques were used to create a Brca2-deficient mouse. A portion of exon 10 was replaced with the Neo gene resulting in premature truncation of the protein product. Examination of normal mammary ductal development in 129(+/+) and 129(+/Brca2- ) mice revealed phenotypic differences between the two genotypic classes. 129(+/+) and 129(+/Brca2- ) mice and several inbred mouse strains were used to study the effect of genetic background on radiation induced mammary tumor induction. BALB/c and SWR mice are susceptible to radiation induced mammary tumorigenesis and C57BL/6, FVB/N and C3H mice are relatively resistant. While FVB/N mice do not develop tumors, radiation treatment has a dramatic effect on ductal morphogenesis. To date, no mammary tumors have been observed in the 129(+/+) and 129(+/Brca2- ) mice. Brca2-deficient mice were crossed to p53 mutant mice to generate four genotypic classes of offspring. A study is in progress to assess the consequences of harboring mutation in the two tumor suppressor genes with and without radiation exposure. The mammary tumor susceptible BALB/c and resistant C57BL/6 mouse strains being used to make mice congenic for the Brca2 mutation.
Download or read book The P53 Protein written by Guillermina Lozano and published by . This book was released on 2016 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Decades of research on the tumor suppressor p53 have revealed that it plays a significant role as a "guardian of the genome," protecting cells against genotoxic stress. In recent years, p53 research has begun to move into the clinic in attempts to understand how p53 is frequently inactivated in-and sometimes even promotes-human cancer. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine covers the rapid progress that has recently been made in basic and clinical research on p53. The contributors review new observations about its basic biology, providing updates on the functions of its isoforms and domains, the myriad stresses and signals that trigger its activation or repression, and its downstream effects on genome stability and the cell cycle that enforce tumor suppression in different cell and tissue types. They also discuss how p53 dysfunction contributes to cancer, exploring the various inherited and somatic mutations in the human TP53 gene, the impact of mutant p53 proteins on tumorigenesis, and the prognostic value and clinical outcomes of these mutations. Drugs that are being developed to respond to tumors harboring aberrant p53 are also described. This book is therefore essential reading for all cancer biologists, cell and molecular biologists, and pharmacologists concerned with the treatment of this disease.
Download or read book Characterization of Two Novel Oncogenic Pathways Collaborating With Loss of P53 Or Activated Neu in Mouse Models of Breast Cancer written by and published by . This book was released on 2005 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer develops through accumulation of multiple genetic mutations. Loss of tumor suppressor gene p53 and activation of oncogene Neu/ErbB2 are among the most frequent genetic alterations in human breast cancer. We performed a retroviral insertional mutagenesis screen to identify genes that may contribute to mammary tumor formation in conjunction with deregulated p53 or Neu. Multiple proviral insertions from independent tumors were identified to be located within introns of the F-box gene Fbw4, suggesting that the structural alteration at this locus may provide selective growth advantage. The viral integrations result in marked overexpression of a novel, naturally occurring Fbw4 short isoform, which is also spontaneously enriched in several mouse and human breast cancer cell lines but not in non-transformed mammary epithelial cells, thus appears to be associated with malignant transformation. Overexpression of this short isoform in the normal mouse mammary epithelial cell leads to anchorage-independent growth in soft agar. Taken together, these observations indicate that aberrant expression of the short Fbw4 isoform observed in MMTV-induced tumors and spontaneous breast cancer cell lines may contribute to mammary tumorigenesis.
Download or read book Characterization of Two Novel Oncogenic Pathways Collaborting With Loss of P53 Or Activated Neu in Mouse Models of Breast Cancer written by and published by . This book was released on 2004 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is a complex multistep disease and progresses through successive accumulation of genetic mutations. Loss of tumor suppressor gene p53 and activation of oncogene Neu/ErB2 are among the most frequent genetic alterations in human breast cancer. We performed a retroviral insertional mutagenesis screen to identify genes that may contribute to mammary tumor formation in conjunction with deregulated p53 or Neu. Multiple proviral insertions from independent tumors were identified to be located within introns of the F-box gene Fbw4, suggesting that the structural alteration at this locus may provide selective growth advantage. The viral integrations result in marked overexpression of a novel, naturally occurring Fbw4 short isoform, which is also spontaneously enriched in several mouse and human breast cancer cell lines but not in non-transformed mammary epithelial cells, thus appears to be associated with malignant transformation. Overexpression of this short isoform in the normal mouse mammary epithelial cell leads to anchorage-independent growth in soft agar. Taken together, these observations indicate that aberrant expression of the short Fbw4 isoform observed in MMTV-induced tumors and spontaneous breast cancer cell lines may contribute to mammary tumorigenesis.
Download or read book Telomeres and Telomerase in Cancer written by Keiko Hiyama and published by Springer Science & Business Media. This book was released on 2009-03-18 with total page 375 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase, an enzyme that maintains telomeres and endows eukaryotic cells with immortality, was first discovered in tetrahymena in 1985. In 1990s, it was proven that this enzyme also plays a key role in the infinite proliferation of human cancer cells. Now telomere and telomerase are widely accepted as important factors involved in cancer biology, and as promising diagnostic tools and therapeutic targets. Recently, role of telomerase in “cancer stem cells” has become another attractive story. Until now, there are several good books on telomere and telomerase focusing on biology in ciliates, yeasts, and mouse or basic sciences in human, providing basic scientists or students with updated knowledge.
Download or read book The BRCA1 Tumor Suppressor Gene in a Mouse Model of Breast Cancer written by and published by . This book was released on 1997 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: BRCA1 is a tumor-suppressor locus on chromosome 17q21. Familial inheritance of a defective copy places a lifetime risk of breast cancer at 80%. Most of these tumors arise before the age of 50. In addition, there is an elevated risk of ovarian and testicular tumors. The mechanism of transformation is not known. In an effort to better understand the actions of this gene, I have cloned the mouse Brca1 gene. The present proposal aims to characterize the effect of over-expression and deletion of Brca1 in mice, and by understanding the nature of the interactions between Brca1 and other oncogenes. The completion of these aims will provide: (1) a mouse model of Brca1 deficiency, (2) an enhanced understanding of Brca1 function in the regulation of mammary epithelial cell growth and differentiation, and (3) reveal important interactions between Brca1 and other potent transforming agents in the breast, in particular with c-myc, and loss of p53.
Download or read book The Role of P53 in Breast Cancer written by Applied Research Applied Research Press and published by . This book was released on 2015-11-07 with total page 164 pages. Available in PDF, EPUB and Kindle. Book excerpt: This article collection reviews the role of p53 in breast cancer and includes 14 open access research papers by various authors. Topics include: Gene expression patterns associated with p53 status in breast cancer; Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress; Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells; Classification of patients with breast cancer according to Nottingham Prognostic Index highlights significant differences in immunohistochemical marker expression; Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations; Expression of full-length p53 and its isoform Delta-p53 in breast carcinomas in relation to mutation status and clinical parameters; The p53 pathway in breast cancer; Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?; Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer; p53 mutant breast cancer patients expressing p53g have as good a prognosis as wild-type p53 breast cancer patients; The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition; Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX; DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival; Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis.
Download or read book A Novel Knock Out Animal Model to Analyze Transcriptional Signaling by P53 Tumor Suppressor Protein in Breast Cancer written by Gokul M. Das and published by . This book was released on 2002 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt: Two important transcriptional targets of p53 tumor suppressor protein are genes encoding the Proliferating Cell Nuclear Antigen (PCNA) and p21/WAF1/Cip1. PCNA is a necessary component of DNA replication and DNA repair machinery. p21/WAF1/Cip1 is a cyclin-dependent kinase (cdk) inhibitor which can interact with PCNA to modulate the balance of DNA repair versus replication. We hypothesize that correct ratio of PCNA and p21 proteins is crucial for normal regulation of DNA repair and cell cycle control, and hence, disregulation of PCNA and p21 transcription in response to genomic damage is an important aspect of breast cancer formation. To test this hypothesis in vivo, we are developing a mouse model where p53 signaling specifically to the PCNA and p21 gene transcription is disrupted. Toward this goal, we are characterizing p53 interaction sites on mouse p21 and PCNA gene promoters (from a series of BAC clones isolated with the help of Poswell Park Cancer Institute Microarray and Genomics Facility). This mouse model will enable testing the relevance of specific transcriptional signaling by p53 to mammary oncogenesis, identification of new therapeutic targets, and analyzing the role of specific p53 transcriptional targets in modulating responses to chemotherapeutic drugs and radiation therapy.
Download or read book Genome Stability written by James Haber and published by Garland Science. This book was released on 2013-12-16 with total page 416 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genome Stability: DNA Repair and Recombination describes the various mechanisms of repairing DNA damage by recombination, most notably the repair of chromosomal breaks. The text presents a definitive history of the evolution of molecular models of DNA repair, emphasizing current research. The book introduces the central players in recombination. An overview of the four major pathways of homologous recombinational repair is followed by a description of the several mechanisms of nonhomologous end-joining. Designed as a textbook for advanced undergraduate and graduate students with a molecular biology and genetics background, researchers and practitioners, especially in cancer biology, will also appreciate the book as a reference.
Download or read book Molecular Oncology of Breast Cancer written by Jeffrey Stuart Ross and published by Jones & Bartlett Learning. This book was released on 2005 with total page 642 pages. Available in PDF, EPUB and Kindle. Book excerpt: The first comprehensive reference to focus on the molecular development and treatment of the disease, Molecular Oncology of Breast Cancer provides authoritative information across the spectrum of modern breast cancer research and clinical care. Edited by two world-class experts in cancer pathology, drug development, and patient management, with contributions from over 50 experts, this ground-breaking text describes the genes, proteins, and biologic pathways that are being evaluated today and will be tested in the future to derive the molecular signature of each newly diagnosed breast cancer. For the first time, readers can now obtain, in a single volume, up-to-date information on how molecular-based tests are being used to identify predisposition, provide earliest detection, decide classification based on genetic fingerprint and predict therapy-specific outcomes. MOBC includes unique chapters on functional imaging and the impact of targeted therapies on the FDA approval process. This book gives readers vital, up-to-date information on important molecular discoveries that affect the everyday management of the breast cancer patient.
Download or read book The Brcal Tumor Suppressor Gene in a Mouse Model of Breast Cancer written by and published by . This book was released on 1999 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: BRCAl is a tumor-suppressor locus on chromosome 17q2l. Familial inheritance of a defective copy places a lifetime risk of breast cancer at 80%. Most of these tumors arise before the age of 50. In addition, there is an elevated risk of ovarian and testicular tumors. The mechanism of transformation is not known. In an effort to better understand the actions of this gene, I have cloned the mouse Brca1 gene. The present proposal aims to characterize the effect of over-expression and deletion of Brcal in mice, and by understanding the nature of the interactions between Brcal and other oncogenes. The completion of these aims will provide: (1) a mouse model of Brcal deficiency, (2) an enhanced understanding of Brca1 function in the regulation of mammary epithelial cell growth and differentiation, and (3) reveal important interactions between Brcal and other potent transforming agents in the breast, in particular with c-m9yc, and loss of p53.
