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Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer
Zongxiang Zhou1, Andrea Flesken-Nikitin, David C Corney
1Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853-6401, USA.
Abstract:
Pathways mediated by p53 and Rb are frequently altered in aggressive human cancers, including prostate carcinoma. To test directly the roles of p53 and Rb in prostate carcinogenesis, we have conditionally inactivated these genes in the prostate epithelium of the mouse. Inactivation of either p53 or Rb leads to prostatic intraepithelial neoplasia developing from the luminal epithelium by 600 days of age. In contrast, inactivation of both genes results in rapidly developing (median survival, 226 days) carcinomas showing both luminal epithelial and neuroendocrine differentiation. The resulting neoplasms are highly metastatic, resistant to androgen depletion from the early stage of development, and marked with multiple gene expression signatures commonly found in human prostate carcinomas. Interestingly, gains at 4qC3 and 4qD2.2 and loss at 14qA2-qD2 have been consistently found by comparative genomic hybridization. These loci contain such human cancer-related genes as Nfib, L-myc, and Nkx3.1, respectively. Our studies show a critical role for p53 and Rb deficiency in prostate carcinogenesis and identify likely secondary genetic alterations. The new genetically defined model should be particularly valuable for providing new molecular insights into the pathogenesis of human prostate cancer.
Insights
Loss of p53 and Rb tumor suppressors drives aggressive prostate cancer in mice. This model reveals critical genetic alterations and pathways involved in prostate carcinogenesis, aiding research into human prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 and Rb tumor suppressor pathways are frequently altered in aggressive human cancers, particularly prostate carcinoma.
- Understanding their specific roles in prostate cancer development is crucial for therapeutic advancements.
Purpose of the Study:
- To investigate the direct roles of p53 and Rb in prostate carcinogenesis using a conditional knockout mouse model.
- To identify secondary genetic alterations and molecular signatures associated with aggressive prostate cancer.
Main Methods:
- Conditional inactivation of p53 and Rb genes in mouse prostate epithelium.
- Monitoring tumor development, differentiation, metastatic potential, and response to androgen depletion.
- Comparative genomic hybridization (CGH) to identify genetic alterations.
- Gene expression profiling to identify molecular signatures.
Main Results:
- Inactivation of either p53 or Rb alone led to prostatic intraepithelial neoplasia.
- Simultaneous inactivation of both p53 and Rb resulted in rapidly progressing, highly metastatic carcinomas with luminal and neuroendocrine differentiation.
- These mouse carcinomas were resistant to androgen depletion and shared gene expression profiles with human prostate carcinomas.
- CGH identified recurrent gains at 4qC3 and 4qD2.2, and loss at 14qA2-qD2, encompassing genes like Nfib, L-myc, and Nkx3.1.
Conclusions:
- p53 and Rb deficiencies play a critical role in prostate carcinogenesis, promoting aggressive tumor development.
- The identified genetic alterations and molecular signatures provide insights into the pathogenesis of human prostate cancer.
- This genetically defined mouse model is a valuable tool for studying prostate cancer mechanisms and developing new therapies.
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