Characterization of Two Novel Oncogenic Pathways Collaborating With Loss of P53 Or Activated Neu in Mouse Models of Breast Cancer PDF Download
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Author:
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Category :
Languages : en
Pages : 8
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Book Description
Cancer is a complex multi step disease and progresses through successive accumulation of 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 gene 5 that my contribute to mammary tumor formation in conjunction with deregulated p53 or Neu. Multiple proviral insertions form 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 Fbw4 short isoform, which is also spontaneously enriched in several mouse and human breast cancer cell lines and thus appears to be associated with tumor formation. Overexpression of this short isoform in the normal' mouse mammary epithelial cell line NMuMg enable these cells to grow in soft agar. Taken together, these findings suggest that Fbw4 in a novel cancer- relevant gene. We propose a mechanism related to Fbw4's oncogenic properties.
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Languages : en
Pages : 8
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Book Description
Cancer is a complex multi step disease and progresses through successive accumulation of 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 gene 5 that my contribute to mammary tumor formation in conjunction with deregulated p53 or Neu. Multiple proviral insertions form 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 Fbw4 short isoform, which is also spontaneously enriched in several mouse and human breast cancer cell lines and thus appears to be associated with tumor formation. Overexpression of this short isoform in the normal' mouse mammary epithelial cell line NMuMg enable these cells to grow in soft agar. Taken together, these findings suggest that Fbw4 in a novel cancer- relevant gene. We propose a mechanism related to Fbw4's oncogenic properties.
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Category :
Languages : en
Pages : 12
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Book Description
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.
Author: Lawrence Donehower
Publisher:
ISBN:
Category :
Languages : en
Pages : 69
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Book Description
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.
Author: Gokul M. Das
Publisher:
ISBN:
Category :
Languages : en
Pages : 16
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Book Description
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.
Author: Trisha Rao
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"The phosphatidylinositol 3' kinase (PI3K)/Akt signalling pathway is activated in several human cancers. PI3K signalling is enhanced by mutations in the p110alpha isoform of PI3K or through loss of negative regulators such as the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). This proto-oncogenic pathway can also be induced in cancer downstream of activated receptor tyrosine kinases such as HER2/ErbB2, which is overexpressed in 30% of breast cancers. In fact, PI3K pathway activation in breast cancer has been associated with resistance to HER2-targeted therapies. In this thesis, we have used transgenic mouse models to investigate the importance of PI3K signalling in ErbB2-mediated mammary tumourigenesis.Our laboratory has previously shown that mammary-specific deletion of Pten can accelerate mammary tumour initiation and metastasis driven by endogenous expression of activated ErbB2. Here, we have validated these findings by demonstrating that Pten loss can cooperate with transgenic overexpression of activated ErbB2 during mammary tumour progression. We have also showed that expression of a constitutively activated p110alpha transgene in the mammary epithelium can enhance the metastatic potential of ErbB2-induced tumours. Conversely, it seems that disruption of PI3K signalling can impair transformation in the mammary gland. We have demonstrated that genetic ablation of p110alpha dramatically delays mammary tumour onset and impairs pulmonary metastasis in mammary tumour models induced by either activated ErbB2 or by the viral oncogene polyomavirus middle T antigen (PyV mT). In order to carry out the latter studies, we generated and characterized a new mouse model of PyV mT-driven mammary tumourigenesis that incorporates temporal and spatial regulation of PyV mT and Cre recombinase expression. Importantly, mammary tumours lacking p110alpha eventually developed after long latencies in both the ErbB2 and PyV mT strains. We have preliminary evidence to suggest that the emergence of some p110alpha-deficient tumours is associated with an upregulation of osteopontin (OPN), a secreted extracellular matrix-associated protein with relevance in breast cancer. We believe that increased OPN expression could be due to enhanced PI3K signalling through non-alpha p110 isoforms, which in turn may be a result of Pten loss.The results from these studies suggest that activation of the PI3K/Akt pathway might collaborate with HER2/ErbB2 signalling in breast cancer progression and malignancy. Although we can conclude from our work that transformation downstream of activated ErbB2 is initially dependent on the alpha isoform of p110, it is likely that patients with HER2-positive breast cancer will eventually encounter resistance to p110alpha-specific inhibitors used as single agents. In these cases, pan PI3K inhibitors may help in preventing the potential reactivation of PI3K signalling through non-targeted p110 isoforms." --
Author:
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ISBN: 9780815332183
Category : Cells
Languages : en
Pages : 0
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Book Description
Author: Jeffrey Stuart Ross
Publisher: Jones & Bartlett Learning
ISBN: 9780763748104
Category : Medical
Languages : en
Pages : 642
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Book Description
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.
Author: Seamus J. Martin
Publisher: S. Karger AG (Switzerland)
ISBN: 9783805565790
Category : Apoptosis
Languages : en
Pages : 0
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Book Description
The past five years have witnessed an explosion of research efforts in the study of how cells die. This book provides an up-to-date overview of our current knowledge of apoptosis and how discoveries in this area impact on our understanding of cancer. By synthesizing many of the recent developments in this area and placing them in perspective, it fulfills an important need. All the contributions are written by experts in their respective fields. The first two chapters give a basic introduction to the cell death machinery and its role in tumor development and progression; subsequent chapters cover current aspects of apoptosis research, including the involvement of cell cycle-related proteins (e.g. cyclin-dependent kinases) in apoptosis, the role of Bcl-2, Bcr-Abl, Rb, p53 and myc in the regulation of cell death, and apoptosis in the context of specific neoplasms such as cancer of the prostate, kidney, leukemia and neuroblastoma. It is also discussed how insights into the regulation of apoptosis may be exploited for designing new drugs aimed at eliminating malignant cells. Compiling the most recent research results on the relationship between apoptosis and cancer in one handy volume, this book will provide a valuable reference for scientists working in cancer research as well as newcomers to the field.
Author: Moshe Oren
Publisher: Springer Science & Business Media
ISBN: 1461462207
Category : Medical
Languages : en
Pages : 345
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Book Description
The Hippo signaling pathway is rapidly gaining recognition as an important player in organ size control and tumorigenesis, and many leading scientists are showing increased interest in this growing field and it's relation to cancer. The chapters in this volume cover virtually all aspects of tumor biology, because members of the Hippo Pathway have been associated with numerous well-established cell signaling pathways, just to name a few; Ras, Wnt, TGFbeta and p53. Moreover, Hippo signaling is not solely involved in regulating “classic” tumor characteristics such as cell proliferation, survival and growth, but is also diversely involved in cell-autonomous and non-cell-autonomous differentiation, migration and organ size control. The primary audience are researchers interested in basic science in the areas of tumor suppression, cell cycle and size regulation, development and differentiation.
Author: United States. Public Health Service. Office of the Surgeon General
Publisher:
ISBN:
Category : Government publications
Languages : en
Pages : 728
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Book Description
This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
