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Loss of  PTEN  is one of the most common mutations in prostate cancer, and loss of wild‐type  TP53  is associated with prostate cancer progression and castrate resistance. Modeling prostate cancer in the mouse has shown that while  Pten  deletion in prostate epithelial cells leads to adenocarcinoma, combined loss of  Pten  and  TP53  results in rapidly developing disease with greater tumor burden and early death.  TP53  contributes significantly to the regulation of stem cell self‐renewal, and we hypothesized that loss of  Pten/TP53  would result in measurable changes in prostate cancer stem/progenitor cell properties. Clonogenic assays that isolate progenitor function in primary prostate epithelial cells were used to measure self‐renewal, differentiation, and tumorigenic potential.  Pten/TP53  null as compared with wild‐type protospheres showed increased self‐renewal activity and modified lineage commitment. Orthotopic transplantation of  Pten / TP53  null cells derived from protospheres produced invasive Prostatic Intraepithelial Neoplasia (PIN)/adenocarcinoma, recapitulating the pathology seen in primary tumors.  Pten / TP53  null progenitors relative to wild type also demonstrated increased dependence on the AKT/mammalian target of rapamycin complex 1 (mTORC1) and androgen receptor (AR) pathways for clonogenic and tumorigenic growth. These data demonstrate roles for  Pten/TP53  in prostate epithelial stem/progenitor cell function, and moreover, as seen in patients with castrate‐resistant prostate cancer, suggest for the involvement of an AR‐dependent axis in the clonogenic expansion of prostate cancer stem cells. STEM CELLS 2010;28:2129–2140

Characterizing the Contribution of Stem/Progenitor Cells to Tumorigenesis in the Pten −/− TP53 −/− Prostate Cancer Model