Download or read book Analysis of Tumor Suppressor Gene Loss in Mouse Mammary Models of Mammary Neoplasia written by Robert Coffey and published by . This book was released on 1998 with total page 9 pages. Available in PDF, EPUB and Kindle. Book excerpt: The original sabbatical proposal was modified to two separate aims, both designed to acquire knowledge of genetics to be applied to mammary carcinoma. These studies were carried out at Stanford University in the laboratories of Stuart Kim, David Botstein and Pat Brown. First, in the Kim lab, a genetic screen was performed in C.elegans in a sensitized background (using worms mutant for Gap) to identify worms that missorted Let-23, the worm EGF receptor, in polarized vulva precursor cells. By complementation testing and STS mapping, a locus has been identified on chromosome 4 that results in missorting of Let-23 from the basolateral to apical surface. Second, microarray technology in the Botstein and Brown labs was utilized to identify sets of genes that are induced by antioxidants in mammary and colorectal carcinoma cells that culminate in p53-independent, p21-dependent apoptosis. Candidate genes have been identified and are being characterized.

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 Dysregulation in Mouse Models of Tumorigenesis written by Timothy James Bowen and published by . This book was released on 2005 with total page 298 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The P53 Deficient Mouse as a Breast Cancer Model written by and published by . This book was released on 1997 with total page 0 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 Genetic Analysis of Tumor Progression in the Mouse Mammary Gland written by Nathan Frederick Schachter and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genetic alterations that cooperate with TP53 mutation in breast cancer (BC) are largely unknown. Using a dominant-negative Trp53LSL-R270H/+ mouse strain, I found Trp53 alteration cooperates with Her2/Neu over-expression, but not with hemizygous deletion of Gata3, Runx1, or Nf1. To identify other genes cooperating with mutant Trp53, I completed a Sleeping Beauty (SB) mutagenesis screen in mice. This identified known cooperators such as Met, and other candidates such as Notch1. Cooperation between activated Notch1 and Trp53LSL-R270H/+ was validated in vivo. In addition to coding mutations, chromosomal copy number changes are also important in BC. To identify genes that contribute to mammary tumorigenesis upon copy number alteration, I compared genes targeted by transposons in SB mice carrying Trp53LSL-R270H/+, R26LSL-Pik3ca(Mut)/+, R26LSL-Stat3C/+, or no mutant allele. This enabled me to identify genes altered in all cohorts (e.g. Rasa1), in several but not all backgrounds (e.g. Met), and those that only occurred in the presence of a single driver (e.g. Mll3, Exoc4, and Cul1 loss in Pik3ca-mutant tumors). Importantly, many genes targeted by SB transposons map to loci syntenic with regions commonly gained/lost in human BC. Thus, they likely represent haploinsufficient tumor suppressors or oncogenes. Guided by SB results, the oncogenic interaction between R26LSL-Pik3ca(Mut)/+ and loss/activation of Notch1 was validated in vivo. Additionally, I distinguished genes altered in metastatic lesions from SB mice. This revealed genes previously implicated in BC dissemination (e.g. Hipk2) and novel abnormalities (e.g. loss of Fbxl17). Lastly, to assess the oncogenic potential of ELF3 (which maps to human chromosome 1q and is frequently gained/amplified in human BC), I generated a Cre-conditional Rosa26-targeted Elf3 transgenic strain (R26LSL-Elf3). Using SB mutagenesis, I showed genes such as Cul5 and FoxP1 were disrupted in Elf3 over-expressing SB mammary tumors, while metastases from these mice selected for a distinct set of insertions (e.g. Pard3 disruption).

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 In Vivo Characterization of Mammalian Polarity Genes as Novel Tumor Suppressors Involved in Breast Cancer Development and Progression in a Mouse Model written by and published by . This book was released on 2006 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: The purpose of our study is to understand the role of novel polarity regulators mammary gland development and their ability to cooperate with oncogenes in tumorogenesis within this gland. We are using mouse systems as well as an analysis of cell lines to understand the role of a particular gene, Scribble, in this process. So far, I have been able to identify one human breast cancer cell line with little scribble expression. In a normal mouse cell line, comma-1D, we are doing further analysis as to the effects of scribble loss using RNAi technology. We have observed a morphological change, with a loss of e-cadherin, as well as a mild proliferative change in scribble knockdown cells. We have also observed a change in lineage specific cytokeratins in these cells. This data is significant as it possibly demonstrates the role of a polarity gene the differentiation of the breast as well as in tumors with concomitant growth changes to the affected tissue.

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 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 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Wnt/ wingless growth factors cause mammary tumors when overexpressed, and have many developmental functions. Yet despite extensive studies on the Wnt ligands, and the putative pathway components, little Is known about the reception mechanisms of signaling by these growth factors. A candidate Wnt receptor has been isolated using the yeast two-hybrid system. This protein has been shown to specifically bind four Wnt ligands. Truncated receptor forms, when misexpressed In Drosophila, lead to wingless loss of function phenotypes, strengthening its legitimacy as a Wnt receptor. The study's long-term objectives is to further characterize and functionally test this gene product. This will involve studies in both mouse and Drosophila, employing both ectopic expression studies and null mutation analysis. The proposed research should verify and elaborate the protein's role in Wnt / wingless signal transduction as it pertains to development and tumorigenesis.

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 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 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 2004 with total page 11 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 and bear germline mutations in TP53. We have used BALB/c-Trp53+/- mice as a model of Li- Fraumeni syndrome to follow the pathogenic changes in mammary glands of BALB/c-Trp53+/- mice and map genes that can alter sensitivity to mammary tumors. Normal mammary tissues from BALB/c-Trp53+/- mice did not reveal gross karyotypic instability or gross hyperproliferative changes. Hyperplastic tissues and intraepithelial neoplasias retained the wild type allele of Trp53 and expressed estrogen receptors. However, transition to invasive lesions was accompanied by a loss of the wild type allele of Trp53 and loss of estrogen receptor. Though BALB/c-Trp53+/- mice develop spontaneous mammary tumors, C57BL/6-Trp53+/- mice are resistant. A genome pan has identified a low-penetrance modifier locus on mouse chromosome 7. Fine mapping of the region of interest is being undertaken.

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.

Download or read book Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland Targeted Bin 1 Knockout Mouse Model written by and published by . This book was released on 2006 with total page 50 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

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 The Use of CDNA Microarray to Study Gene Expression in Wnt 1 Induced Mammary Tumors written by and published by . This book was released on 2002 with total page 23 pages. Available in PDF, EPUB and Kindle. Book excerpt: To understand the multi-step process of mammary tumorigenesis, we have compared gene expression profiles in different stages of mammary oncogenesis in MMTV-Wnt- 1 transgenic mice. Specifically, we have collected tissue samples from virgin mammary glands, hyperplastic mammary glands, Wnt- 1 mammary tumors, and tumors metastasized to the lung, and compared their gene expression patterns. Hierarchical clustering analysis and multidimensional scaling analysis showed that gene expression profiles are associated with tumor progression. Each sample group from the same stage cluster separately from samples at other stages. Using the statistical analysis permutation t-test, I identified groups of genes differentially expressed in each of the stages. I also identified a group of genes as potential direct or indirect target genes of Wnt signaling since they are only regulated in mammary tumors induced by the MMTV-Wnt-1 transgene in comparison with tumors induced by other transgenes such as (MMTV)-c-myc, MMTV-Ha-ras, MMTV-neu, MMTV-polyoma middle T antigen, C3(l)/simian virus 40 T/t antigen, and WAP-SV4O T/t antigen (Desai et al., 2002). In addition, I established gene expression profiles for mammary tumors induced by Wntl, and by Wnt1 in cooperation with loss of tumor suppressor genes such as Pten or P53.

Download or read book Tumor Suppressor Mechanism in Breast Cancer Studies in Genetically Engineered Mice written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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. The mechanisms by which p53 and pRb suppress tumorigenesis in breast cancer remain unclear. Our previous studies in a mouse brain epithelial tumor model have demonstrated the importance of pRb in tumor initiation and of p53 in tumorprogression, and have also 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 modified T antigen oncoprotein that inactivates pRb. This causes slow-growing, but highly apoptotic tumors. Further inactivation of p53 causes a dramatic decline in cell teath and rapid acceleration of tumor growth. Here, 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 T121 oncoprotein will be tissue-specifically expressed in mammary epithelium by mammary-specific promoters to test the role of pRb. Further analysis using knock out strains will then address the role of p53 when both pRb and p53 are inactivated. Impacts of the pRb inactivation, and of coexisting pRb and p53 mutations on apoptosis, proliferation, morphology abnormalities, and neoplastic growth in mammary glands will be assessed. Such preclinical animal models are essential for progress in breast cancer research. The approach proposed here is novel because the role of pRb has not previously been tested and the p53 tumor suppression mechanism in breast cancer is not yet understood.