Tumor Suppressor Mechanism in Breast Cancer: Studies in Genetically Engineered Mice PDF Download
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Languages : en
Pages : 16
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The p53 and pRb tumor suppressor pathways are frequently altered in human breast cancer. Although animal models have begun to explore mechanisms for these proteins, the roles can be different depending on the cancer type. Our previous studies in a mouse brain epithelial tumor model have demonstrated the importance of pRb in tumor initiation and of p53 in tumor progression, and have established p53-dependent apoptosis as a means of tumor suppression. In this model, brain cells are induced to proliferate aberrantly by tissue-specific expression of T121, a small T antigen oncoprotein that inactivates pRb. This causes slow growing, but highly apoptotic tumors. Further inactivation of p53 causes a dramatic decline in cell death and rapid acceleration of tumor growth. We propose similar studies to examine the pRb and p53 roles in breast cancer. The full T antigen oncoprotein (inactivates both pRb and p53) has been shown to induce mammary tumors in transgenic mice. Here, the T - oncoprotein will be tissue-specifically expressed in mammary epithelium by mammary-specific promoters to test the role of pRb.
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Languages : en
Pages : 16
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The p53 and pRb tumor suppressor pathways are frequently altered in human breast cancer. Although animal models have begun to explore mechanisms for these proteins, the roles can be different depending on the cancer type. Our previous studies in a mouse brain epithelial tumor model have demonstrated the importance of pRb in tumor initiation and of p53 in tumor progression, and have established p53-dependent apoptosis as a means of tumor suppression. In this model, brain cells are induced to proliferate aberrantly by tissue-specific expression of T121, a small T antigen oncoprotein that inactivates pRb. This causes slow growing, but highly apoptotic tumors. Further inactivation of p53 causes a dramatic decline in cell death and rapid acceleration of tumor growth. We propose similar studies to examine the pRb and p53 roles in breast cancer. The full T antigen oncoprotein (inactivates both pRb and p53) has been shown to induce mammary tumors in transgenic mice. Here, the T - oncoprotein will be tissue-specifically expressed in mammary epithelium by mammary-specific promoters to test the role of pRb.
Author: Leah Marie Cook
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Languages : en
Pages : 150
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Category :
Languages : en
Pages : 352
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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.
Author: Eric C. Holland
Publisher: John Wiley & Sons
ISBN: 047144460X
Category : Science
Languages : en
Pages : 504
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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.
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Languages : en
Pages : 0
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ING1 is recently isolated breast cancer candidate tumor suppressor gene. In this study, structure and expression of the mouse ing1 gene were analyzed. Ing1 is transcribed from three differently regulated promoters. Each of the resulting transcripts represents two exons; they share a long common region encoded by a common exon and differ in their 5'-exon sequences encoded by alternative 5'-exons. Three alternative transcripts of ing1 encode two proteins one of which is a truncated version of the other. Protein sequences encoded by mouse and human ing1 are highly conserved. Expression of ing1 mRNA expression correlates with cell proliferation suggesting a connection between cell growth regulation and ing1 expression. Embryonic stem cells with heterozygous deletion of ing1 common exon are prepared as a first step in the generation of ing1 knockout mice. Analysis of ing1 knockout animals should give important information about the role ing1 might have in carcinogenesis.
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Languages : en
Pages : 11
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Growth factors transmit their signal by binding a receptor and activating a cascade of downstream events that eventually leads to cellular proliferation; normal or abberant. With regard to the Wnt I wingless family of growth factors / oncogenes, little is known about the receptor(s) or reception mechanism(s) involved. The present study may shed light on a key piece of this puzzle and unravel how Wnts cause cellular growth, often leading to tumorigenesis.
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Languages : en
Pages : 0
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Tumor suppressor MMACl/PTEN/TEPl is considered related with breast cancer formation or progression due to a collective evidence of mutant MMAC 1 in various advanced cancers, especially breast carcinoma. Our preliminary data as well as results of most recent study have provided further evidence of MMAC 1 regulation on PI3K pathway signaling and cell activities, such as cell growth and survival. Our observation of differential modulation of MMAC1 on protein tyrosine phosphorylation in cells indicates a complex role of MMAC1 in multiple cell signals. Thus, the established MMAC 1 transgenic mice model will undoubtedly help to determine the role of MMACl in mammary development and tumorigenesis in vivo.
Author: Surajit Pathak
Publisher: Springer Nature
ISBN: 9811938245
Category : Medical
Languages : en
Pages : 1158
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This reference book compiles together different animal models in cancer research. It provides knowledge and a better understanding of the advancement of the molecular and cellular mechanisms associated with the progression, formation, and clinical results of various types of cancer from the evidence collected from animal models utilized for cancer research. It discusses animal models for screening anti-cancer drugs and exploration of gene therapy. It presents different methods used to construct cancer animal models and the progress of each animal model in tumor research. The book also highlights the applications of genetic engineering, including CRISP/Cas9, in designing and developing animal models for cancer research. Further, it discusses strategies for modeling animals for investigating growth, metastasis, tumor-associated inflammation and microenvironment, cancer stem cells, tumor heterogeneity, and therapeutic resistance. This book is s a valuable resource for basic and translational cancer researchers, clinicians, and health care.
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Languages : en
Pages : 50
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Bin1 is implicated to be anti-cancer gene in mammary gland epithelial cells. We have discovered that Bin1 loss can promote tumorigenesis through a cell-extrinsic mechanism that involves escape from host cell-mediated anti-tumor immunity. This correlates with the negative regulatory impact that Bin1 exerts on the important immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). We have demonstrated how, in combination with certain standard chemotherapeutic agents, inhibitors of IDO can be successfully employed in a non-obvious therapeutic regimen to successfully treat established tumors in MMTV-Neu mice -- an autochthonous breast cancer model histologically akin to ductal carcinoma in situ (DCIS). We have shown that these tumors respond to IDO inhibitor treatment in combination with certain chemotherapeutics, but do not know if this is due to inhibiting IDO that is directly expressed in the tumor cells or in accessory antigen presenting cells (APCs). The studies we are conducting directly interrogate the role of Bin1 loss and concomitant IDO upregulation in the development of autochthonous breast tumors. To this end, we have developed antibodies that will allow us to immuno-histochemically evaluate Bin1 and IDO expression in tumors. Furthermore, we have developed a conditional Bin1 knockout mouse, which will allow us to target Bin1 deletion specifically to the mammary gland epithelium. In conjunction with the bioavailable inhibitor 1-methyl-tryptophan (1MT), we are using a combination of genetic and chemical genetic approaches to establish the pathophysiological relevance of this pathway to mammary gland tumor biology and begin to elucidate the cellular mechanisms by which tumors escape immune rejection.
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ISBN: 9780815332183
Category : Cells
Languages : en
Pages : 0
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