Characterization of Wnt-1 Transgenic Mice (with and Without P53-deficiency) as Models of Spontaneous Mammary Tumorigenesis for Chemoprevention Studies PDF Download
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Languages : en
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Wnt-1 transgenic(TG) mice develop mammary tumors at a high rate by 1 year of age due to mammary gland overexpression of the Wnt-1 oncogene. - We have shown that p53-deficiency accelerates mammary tumorigenesis in these mice, with 100% of p53-1- Wnt-1 TG mice and p53+/-Wnt-1 TG mice dead from mammary tumors by 5 months and 9 months of age, respectively. To test their response to cancer preventive regimens, we randomized 104 female p53+/- Wnt-1 TG mice (5 weeks of age, 20 mice/treatment) to receive: 1) control diet (AIN-76A diet); 2) fenretinide (AIN 76A diet with 0.04% w/w fenretinide); 3) fluasterone (AIN- 76A diet with 0.2% fluasterone); 4) soy (AIN-76A diet with 0.45% phytochemical-enriched soy extract); or 5) a calorie restriction regimen (40% reduction in carbohydrate calorie intake relative to the control group). All mice were euthanized once a tumor reached 1.5 cm in diameter. We found that, relative to the control group (MTD=15.7 weeks), the fenretinide (MTD=23.1 weeks, p=O. Ol) and fluasterone (MTD=23.l weeks, p=O.006) and soy (MTD =21 weeks, p=O.04) groups displayed moderate but significant delays in tumor development and death, while the calorie restricted group (MTD> 40 weeks; p
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Languages : en
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Wnt-1 transgenic(TG) mice develop mammary tumors at a high rate by 1 year of age due to mammary gland overexpression of the Wnt-1 oncogene. - We have shown that p53-deficiency accelerates mammary tumorigenesis in these mice, with 100% of p53-1- Wnt-1 TG mice and p53+/-Wnt-1 TG mice dead from mammary tumors by 5 months and 9 months of age, respectively. To test their response to cancer preventive regimens, we randomized 104 female p53+/- Wnt-1 TG mice (5 weeks of age, 20 mice/treatment) to receive: 1) control diet (AIN-76A diet); 2) fenretinide (AIN 76A diet with 0.04% w/w fenretinide); 3) fluasterone (AIN- 76A diet with 0.2% fluasterone); 4) soy (AIN-76A diet with 0.45% phytochemical-enriched soy extract); or 5) a calorie restriction regimen (40% reduction in carbohydrate calorie intake relative to the control group). All mice were euthanized once a tumor reached 1.5 cm in diameter. We found that, relative to the control group (MTD=15.7 weeks), the fenretinide (MTD=23.1 weeks, p=O. Ol) and fluasterone (MTD=23.l weeks, p=O.006) and soy (MTD =21 weeks, p=O.04) groups displayed moderate but significant delays in tumor development and death, while the calorie restricted group (MTD> 40 weeks; p
Author: Lawrence Donehower
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Languages : en
Pages : 69
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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: Deepa Bhavani Shankar
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Languages : en
Pages : 334
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Mouse mammary tumor virus (MMTV) is used as an insertion mutagen in transgenic mice that express the Wnt1 gene in their mammary gland, to produce additional events like activation of a second oncogene. Cloning cellular sequences flanking new proviral insertion from tumor 76 identified a common insertion locus for MMTV. Further analyses of this region identified Fgf3 as the gene activated over a long distance by MMTV. Fgf8 is another oncogene that I identified was activated in 10% of the mammary tumors form these infected Wnt1 transgenic mice. Fgf8 encodes for at least seven different protein isoforms, three of which were isolated by us. These three isoforms (Fgf8a, b & c) differ in their NIH3T3 cell transforming abilities. Fgf8b induces programmed cell death of mammary epithelial cells. This apoptotic property is not confined to Fgf8b but is also seen when mammary epithelial cells are treated with purified human FGF proteins (FGF 1, 2, 4, 6, & 9). Over expression of BCL2 in the mammary epithelial cells delays the onset of FGF induced apoptosis. Female transgenic mice expressing the Fgf8 gene in the mammary gland developed tumors with a latency of 5-6 months. These tumors were found to be adenocarcinomas: benign adenomas to invasive ductal carcinomas. Northern analyses of tumor RNAs show high expression of the transgene.
Author: Deepa Shankar
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Languages : en
Pages : 0
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Mouse mammary tumor virus (MMTV) is used as an insertion mutagen in transgenic mice that express the Wnt1 gene in their mammary gland, to produce additional events like activation of a second oncogene. Cloning cellular sequences flanking new proviral insertion from tumor 76 identified a common insertion locus for MMTV. Further analyses of this region identified Fgf3 as the gene activated over a long distance by MMTV. Fgf8 is another oncogene that I identified was activated in 10% of the mammary tumors form these infected Wnt1 transgenic mice. Fgf8 encodes for at least seven different protein isoforms, three of which were isolated by us. These three isoforms (Fgf8a, b & c) differ in their NIH3T3 cell transforming abilities. Fgf8b induces programmed cell death of mammary epithelial cells. This apoptotic property is not confined to Fgf8b but is also seen when mammary epithelial cells are treated with purified human FGF proteins (FGF 1, 2, 4, 6, & 9). Over expression of BCL2 in the mammary epithelial cells delays the onset of FGF induced apoptosis. Female transgenic mice expressing the Fgf8 gene in the mammary gland developed tumors with a latency of 5-6 months. These tumors were found to be adenocarcinomas: benign adenomas to invasive ductal carcinomas. Northern analyses of tumor RNAs show high expression of the transgene.
Author: Yvonne Mark
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Languages : en
Pages : 84
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Category : Cancer
Languages : en
Pages : 444
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Languages : en
Pages : 21
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We have generated and characterized several mouse models to better understand the role of breast cancer associated genes in an e
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Category : Cancer
Languages : en
Pages : 76
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Languages : en
Pages : 16
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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.
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Languages : en
Pages : 12
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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.
