Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

Martin, Keith R; Jokinen, Micheal P.; Honeycutt, Hayden P.; Quinn, Anita; Kari, Frank W.; Barrett, J. Carl; French, John E.

doi:10.1080/01926230490462129

Cited by 2 publications

(1 citation statement)

References 29 publications

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“…SV40 Tag blocks both the RB and TP53 pathways, and because loss of RB or TP53 function alone does not drive the neuroendocrine phenotype, the simultaneous loss of both genes may be an essential step for neuroendocrine differentiation. [32][33][34] This hypothesis is supported by observations of other human neuroendocrine carcinomas, as well as neuroendocrine carcinoma models. For instance, 90% of human small cell cancers of the lung (a neuroendocrine carcinoma) have inactivation of both RB and TP53.…”

Section: 26supporting

confidence: 74%

Dissociation of Epithelial and Neuroendocrine Carcinoma Lineages in the Transgenic Adenocarcinoma of Mouse Prostate Model of Prostate Cancer

Chiaverotti

Couto

Donjacour

et al. 2008

The American Journal of Pathology

208

242

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The transgenic adenocarcinoma of mouse prostate (TRAMP) model is widely used in prostate cancer research because of rapid tumor onset and progression. The transgenic mouse is on a C57BL/6 (B6) background and expresses SV40 T-antigen under the probasin promoter. The strong genetic component of susceptibility to prostate cancer in humans prompted us to investigate the effect of mouse strain background (FVB and B6) on incidence, progression, and pathology of prostate cancer in this model. Because TRAMP lesions are unique but differ from conventional prostatic intraepithelial neoplasia because the epithelium and stroma are affected diffusely, we designated them as "atypical hyperplasia of Tag." Although the incidence and severity of atypical hyperplasia of Tag is similar, FVB-TRAMP mice live significantly shorter lives than B6-TRAMP mice because of the rapid development and progression of neuroendocrine carcinomas. This is associated with an increased frequency of neuroendocrine precursor lesions in young TRAMP mice, detectable at 4 weeks after birth. These lesions show properties of bipotential stem cells and co-express markers of epithelial (E-cadherin) and neuroendocrine (synaptophysin) lineages, as well as the transcription factors Foxa1 and Foxa2. Transplantation studies using TRAMP prostatic ducts suggested that neuroendocrine carcinomas arise independently from atypical hyperplasias or other epithelial lesions. Adenocarcinomas were not seen in our cohort. Thus, neuroendocrine Prostate cancer is the most frequently diagnosed cancer in men living in the United States and the second leading cause of cancer-related mortality, accounting for more than 29,000 deaths annually. The causes of this high incidence are unknown, but include both environmental factors and a genetic component.

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Section: 26supporting

confidence: 74%

Dissociation of Epithelial and Neuroendocrine Carcinoma Lineages in the Transgenic Adenocarcinoma of Mouse Prostate Model of Prostate Cancer

Chiaverotti

Couto

Donjacour

et al. 2008

The American Journal of Pathology

208

242

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Tumor Profile of Novel p53 Heterozygous Tg.AC (v-Ha-ras) Bitransgenic Mice Treated with Benzo(a)pyrene and Fed Dietary N-acetyl-L-cysteine (NAC)

Martin

Jokinen²,

Honeycutt³

et al. 2004

Toxicological Sciences

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We designed a novel short-term bitransgenic model to better characterize the effects of benzo(a)pyrene (BP) exposure on multi-organ carcinogenesis and to evaluate the effects of a well-recognized antioxidant, N-acetyl-L-cysteine (NAC), on neoplasia. We selected the p53 heterozygous Tg.AC (v-Ha-ras) mouse model for our studies because these mice possess a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele. Both mutations occur frequently in human cancers. In a 2 x 2 experimental design, both female and male mice were fed basal diet alone or containing 3% NAC and administered by gavage corn oil vehicle alone or containing 20 mg BP/kg body weight given twice weekly for 10 weeks. Mice (n = 15 for each grouping and sex) were subsequently observed an additional 18 weeks followed by tissue collection for evaluation of multi-organ pathology. Benzo(a)pyrene increased neoplasia in the thymus, spleen, stomach, and hematopoietic system after 28 weeks. We observed modest NAC-associated decreases in BP-induced pathology of the liver, papilloma formation and hyperplasia in the forestomach, and the occurrence of malignant lymphoma. Benzo(a)pyrene exposure reduced survival to approximately 40% in male mice, suggesting toxicity; however, survival in control groups was approximately 60%. Survival decreased to approximately 30% for females in all groups. We noted a clear, but nonsignificant, 15% decline in body weights of male, but not female, mice fed NAC, although food intake did not differ. Collectively, the data suggested carcinogen and antioxidant-associated effects on neoplasia that appeared sex-dependent. Thus, this novel short-term bitransgenic model may potentially be useful for testing dietary modulation of carcinogenesis.

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Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

Cited by 2 publications

References 29 publications

Dissociation of Epithelial and Neuroendocrine Carcinoma Lineages in the Transgenic Adenocarcinoma of Mouse Prostate Model of Prostate Cancer

Dissociation of Epithelial and Neuroendocrine Carcinoma Lineages in the Transgenic Adenocarcinoma of Mouse Prostate Model of Prostate Cancer

Tumor Profile of Novel p53 Heterozygous Tg.AC (v-Ha-ras) Bitransgenic Mice Treated with Benzo(a)pyrene and Fed Dietary N-acetyl-L-cysteine (NAC)

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