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Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate

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Abstract

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison with mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master regulator analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a coregulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways.

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Acknowledgements

This work was supported by Public Health Service grants, R01CA070297, R01CA166894, R21CA190021, and R01DK104941.

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Author notes

  1. These five authors contributed equally: Yongfeng He, Daniel T. Johnson, Julie S. Yang, Huiqing Wu, Sungyong You

Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA

    Yongfeng He, Julie S. Yang, Dong-Hoon Lee, Won Kyung Kim, Joseph Aldahl, Vien Le, Erika Hooker, Eun-Jeong Yu & Zijie Sun

  2. Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, USA

    Yongfeng He, Daniel T. Johnson, Erika Hooker, Eun-Jeong Yu & Zijie Sun

  3. Department of Pathology, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA

    Huiqing Wu

  4. Division of Cancer Biology and Therapeutics, Departments of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Sungyong You & Junhee Yoon

  5. Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA

    Joseph Geradts

  6. Center for Comparative Medicine, University of California at Davis, 4115 Primate Research Drive, Davis, CA, 95616, USA

    Robert D. Cardiff

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  1. Yongfeng He
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Correspondence to Zijie Sun.

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He, Y., Johnson, D.T., Yang, J.S. et al. Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate. Oncogene 38, 6507–6520 (2019). https://doi.org/10.1038/s41388-019-0901-8

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