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Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma.

ABSTRACT: The middle T (MT) antigen of polyomavirus has provided fundamental insights into the regulation of mammalian cell growth in vitro and important animal models for the analysis of tumor induction. The mouse mammary tumor virus (MMTV)-MT model of breast cancer has been important for probing the cellular signaling pathways in mammary tumorigenesis. MT itself has no intrinsic enzymatic activity but, rather, transforms by binding to and activating key intracellular signaling molecules, phosphatidylinositol 3-kinase (PI3-kinase) being the best studied of these. Thus, MT mimics a constitutively activated receptor tyrosine kinase (RTK). Our recent work suggests that MT signaling, like that of RTKs, is often quite dependent on cellular context in vitro. Here, we examine contextual effects on signaling in animal models as well. In this study, we generated transgenic mice in which MT is expressed in the mouse prostate under the control of an (ARR)2-Probasin promoter. All male transgenic mice displayed mouse prostatic intraepithelial neoplasia (mPIN) in the ventral and dorsal/lateral prostate as early as 8 weeks of age. Notably, during the course of tumor development over time, invasive cancer, reactive stroma, and infiltration of inflammatory cells were seen. Transcriptional profiling analyses show regulation of multiple pathways, with marked upregulation of both the NF-?B and inflammatory pathways. Comparison of expression profiles of our MT prostate model with those from an MMTV-MT breast model (23) shows both tissue-specific and tissue-independent MT effects. The signature of genes regulated by MT in a tissue-independent manner may have prognostic value.

SUBMITTER: Lee SH

PROVIDER: S-EPMC3094993 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma.

Lee Sang Hyun SH Jia Shidong S Zhu Yanni Y Utermark Tamara T Signoretti Sabina S Loda Massimo M Schaffhausen Brian B Roberts Thomas M TM

Journal of virology 20110316 11

The middle T (MT) antigen of polyomavirus has provided fundamental insights into the regulation of mammalian cell growth in vitro and important animal models for the analysis of tumor induction. The mouse mammary tumor virus (MMTV)-MT model of breast cancer has been important for probing the cellular signaling pathways in mammary tumorigenesis. MT itself has no intrinsic enzymatic activity but, rather, transforms by binding to and activating key intracellular signaling molecules, phosphatidylino ...[more]

PMID: 21411524

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Project description:IntroductionEffective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans. We sought to engineer a novel mouse model of polyomavirus middle T antigen (PyV mT)-mediated mammary tumourigenesis in which inducible expression of this well-characterized viral oncoprotein is coupled to Cre recombinase (TetO-PyV mT-IRES-Cre recombinase or MIC).MethodsMIC mice were crossed to the mouse mammary tumour virus (MMTV)-reverse tetracycline transactivator (rtTA) strain to generate cohorts of virgin females carrying one or both transgenes. Experimental (rtTA/MIC) and control (rtTA or MIC) animals were administered 2 mg/mL doxycycline beginning as early as eight weeks of age and monitored for mammary tumour formation, in parallel with un-induced controls of the same genotypes.ResultsOf the rtTA/MIC virgin females studied, 90% developed mammary tumour with complete penetrance to all glands in response to doxycycline and a T50 of seven days post-induction, while induced or un-induced controls remained tumour-free after one year of induction. Histological analyses of rtTA/MIC mammary glands and tumour revealed that lesions followed the canonical stepwise progression of PyV mT tumourigenesis, from hyperplasia to mammary intraepithelial neoplasia/adenoma, carcinoma, and invasive carcinoma that metastasizes to the lung; at each of these stages expression of PyV mT and Cre recombinase transgenes was confirmed. Withdrawal of doxycycline from rtTA/MIC mice with end-stage mammary tumours led to rapid regression, yet animals eventually developed PyV mT-expressing and -non-expressing recurrent masses with varied tumour histopathologies.ConclusionsWe have successfully created a temporally regulated mouse model of PyV mT-mediated mammary tumourigenesis that can be used to study Cre recombinase-mediated genetic changes simultaneously. While maintaining all of the hallmark features of the well-established constitutive MMTV-PyV mT model, the utility of this strain derives from the linking of PyV mT and Cre recombinase transgenes; mammary epithelial cells are thereby forced to couple PyV mT expression with conditional ablation of a given gene. This transgenic mouse model will be an important research tool for identifying synthetic viable genetic events that enable PyV mT tumours to evolve in the absence of a key signaling pathway.

Project description:Severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in hepatic injury remains a contentious topic. We found that ductular reaction cells in human cirrhotic livers express hepatocyte nuclear factor 1 homeobox B (HNF1?). However, HNF1? expression was not present in newly generated epithelial cell adhesion molecule (EpCAM)-positive hepatocytes. In order to investigate the role of HNF1?-expressing cells we used a tamoxifen-inducible Hnf1?CreER/R26R(Yfp/LacZ) mouse to lineage-trace Hnf1?(+) biliary duct cells and to assess their contribution to LPC expansion and hepatocyte generation. Lineage tracing demonstrated no contribution of HNF1?(+) cells to hepatocytes during liver homeostasis in healthy mice or after loss of liver mass. After acute acetaminophen or carbon tetrachloride injury no contribution of HNF1?(+) cells to hepatocyte was detected. We next assessed the contribution of Hnf1?(+) -derived cells following two liver injury models with LPC expansion, a diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet and a choline-deficient ethionine-supplemented (CDE)-diet. The contribution of Hnf1?(+) cells to liver regeneration was dependent on the liver injury model. While no contribution was observed after DDC-diet treatment, mice fed with a CDE-diet showed a small population of hepatocytes derived from Hnf1?(+) cells that were expanded to 1.86% of total hepatocytes after injury recovery. Genome-wide expression profile of Hnf1?(+) -derived cells from the DDC and CDE models indicated that no contribution of LPC to hepatocytes was associated with LPC expression of genes related to telomere maintenance, inflammation, and chemokine signaling pathways.HNF1?(+) biliary duct cells are the origin of LPC. HNF1?(+) cells do not contribute to hepatocyte turnover in the healthy liver, but after certain liver injury, they can differentiate to hepatocytes contributing to liver regeneration.

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Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma.

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Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma.

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