Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice

Krepulat, Frauke; Löhler, Jürgen; Heinlein, Christina; Hermannstädter, Andrea; Tolstonog, Genrich V.; Deppert, Wolfgang

doi:10.1038/sj.onc.1208557

Cited by 26 publications

(36 citation statements)

References 57 publications

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“…Comparison of size, localization and onset of the tumors did not show any correlation. Tumors with volumes greater than 1 cm 3 were found in cervical, thoracal, abdominal as well as in inguinal mammary glands and all tumors became increasingly irregular in shape during development. Figure 1 focuses on a representative WAP-T transgenic mouse and demonstrates the use of contrastenhanced fpVCT to visualize all mammary carcinomas that developed in this mouse over time.…”

Section: Determination Of Growth Rates Of Multiple Mammary Carcinomasmentioning

confidence: 99%

“…In this mouse, 6 mammary carcinomas developed at distinct times with differences up to 40 days in divergent mammary glands, reaching tumor volumes between 0.004 and 1.227 cm 3 at the end of the experiment. Their growth kinetics were comparable up to a tumor volume of 0.2 cm 3 . Because of early detection, tumor progression could be monitored by fpVCT over a long period of time, even up to 90 days.…”

Section: Determination Of Growth Rates Of Multiple Mammary Carcinomasmentioning

confidence: 99%

“…One promising model in addressing such questions is the WAP-T transgenic mouse. [2][3][4] In these mice, the SV40 early gene region is induced specifically in differentiating mammary epithelial cells upon activation of the WAPpromoter during late pregnancy and lactation, and drives mammary carcinogenesis in mammary epithelial cells re-expressing the transgene after involution of the mammary glands. The SV40 early region mainly serves to functionally eliminate the p53 and pRb tumor suppressors by binding to the SV40 large T-antigen 5 and to change the specificity of the phosphatase PP2A 6 by its interaction with SV40 small T-antigen, thereby initiating tumor development.…”

Section: Uiccmentioning

confidence: 99%

“…Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm 3 ) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice.…”

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confidence: 99%

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Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Jannasch

Dullin

Heinlein

et al. 2009

Intl Journal of Cancer

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Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm 3 ) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. ' UICCKey words: flat-panel volume computed tomography; in vivo imaging; murine transgenic tumor models; tumor angiogenesis Accompanying the rapid progress in deciphering the human and mouse genome, many transgenic mouse models have been generated. Weissleder and Mahmood already assumed in 2001 that more than 25 million transgenic and knockout mice would be raised that year for experimental studies, accounting for over 90% of all mammals in research.1 These mouse models offer the opportunity to study gene functions in their biological context in a much more physiological way than any other approach. Especially cancer research benefits from the advantages of these transgenic mice in elucidating the role of a specific gene in tumor growth and spread as well as angiogenesis. One promising model in addressing such questions is the WAP-T transgenic mouse. [2][3][4] In these mice, the SV40 early gene region is induced specifically in differentiating mammary epithelial cells upon activation of the WAPpromoter during late pregnancy and lactation, and drives mammary carcinogenesis in mammary epithelial cells re-expressing the transgene after involution of the mammary glands. The SV40 early region mainly serves to functionally eliminate the p53 and pRb tumor suppressors by binding to the SV40 large T-antigen 5 and to change the specificity of the phosphatase PP2A 6 by its interaction with SV40 small T-antigen, thereby...

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Section: Determination Of Growth Rates Of Multiple Mammary Carcinomasmentioning

confidence: 99%

Section: Determination Of Growth Rates Of Multiple Mammary Carcinomasmentioning

confidence: 99%

Section: Uiccmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Jannasch

Dullin

Heinlein

et al. 2009

Intl Journal of Cancer

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“…60 The use of the whey acidic protein promoter allowed for the targeted expression of both transgenes in the mammary epithelium. 61,62 In this double transgenic model, binding of SV40-LT to p53…”

Section: Is Gof a Consequence Of Unusual Protein Interactions?mentioning

confidence: 99%

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

et al. 2010

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Three decades of p53 research have led to many advances in understanding the basic biology of normal and cancer cells. Nonetheless, the detailed functions of p53 in normal cells, and even more so in cancer cells, remain obscure. A major breakthrough is the realization that mutant p53 has a life of its own: it contributes to cancer not only through loss of activity, but also through gain of specific 'mutant functions'. This new focus on mutant p53 is the rationale behind the meeting series dedicated to advances on mutant p53 biology. This review provides an overview of results presented at the Fourth International Workshop on Mutant p53, held in Akko, Israel in March 2009. New roles and functions of p53 relevant for tumor suppressions were presented, including the regulation of microRNAs networks, the modulation of cell-stroma interactions and the induction of senescence. A main focus of the meeting was the rapidly growing body of knowledge on autonomous properties of mutant p53 and on their oncogenic 'gain of function' impact. Importantly, the meeting highlighted that, 30 years after p53 discovery, research on mutant p53 is entering the clinical and translational era. Two major steps forward in this respect are a better understanding of the active mechanism of small drugs targeting mutant p53 in tumor cells and an improved definition of the prognostic and predictive value of mutant p53 in human cancer.

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Mutant p53^R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis

Heinlein

Krepulat

Löhler

et al. 2007

Intl Journal of Cancer

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In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild-type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP-T mice). In such tumors the endogenous wild-type p53 is functionally compromised by complex formation with SV40 T-antigen, thereby constituting a loss of wild-type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi-transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. ' 2007 Wiley-Liss, Inc.

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Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice

Cited by 26 publications

References 57 publications

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

Mutant p53^R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis

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Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice

Cited by 26 publications

References 57 publications

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

Mutant p53R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis

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Mutant p53^R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis