Research Papers:

Deletion of tumor suppressors adenomatous polyposis coli and Smad4 in murine luminal epithelial cells causes invasive prostate cancer and loss of androgen receptor expression

Kenneth C. Valkenburg _, Angelo M. De Marzo and Bart O. Williams

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Oncotarget. 2017; 8:80265-80277. https://doi.org/10.18632/oncotarget.17919

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Kenneth C. Valkenburg1, Angelo M. De Marzo2,3 and Bart O. Williams1

1Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA

2Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

3Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

Correspondence to:

Kenneth C. Valkenburg, email: [email protected]

Keywords: mouse model, prostate cancer, basaloid, squamous, Apc

Received: November 01, 2016     Accepted: May 03, 2017     Published: May 17, 2017


Prostate cancer is the most diagnosed non-skin cancer in the US and kills approximately 27,000 men per year in the US. Additional genetic mouse models are needed that recapitulate the heterogeneous nature of human prostate cancer. The Wnt/beta-catenin signaling pathway is important for human prostate tumorigenesis and metastasis, and also drives tumorigenesis in mouse models. Loss of Smad4 has also been found in human prostate cancer and drives tumorigenesis and metastasis when coupled with other genetic aberrations in mouse models. In this work, we concurrently deleted Smad4 and the tumor suppressor and endogenous Wnt/beta-catenin inhibitor adenomatous polyposis coli (Apc) in luminal prostate cells in mice. This double conditional knockout model produced invasive castration-resistant prostate carcinoma with no evidence of metastasis. We observed mixed differentiation phenotypes, including basaloid and squamous differentiation. Interestingly, tumor cells in this model commonly lose androgen receptor expression. In addition, tumors disappear in these mice during androgen cycling (castration followed by testosterone reintroduction). These mice model non-metastatic castration resistant prostate cancer and should provide novel information for tumors that have genetic aberrations in the Wnt pathway or Smad4.

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