Prostate cancers display a range of clinical behavior, from slow-growing tumors of minor clinical significance to locally aggressive and ultimately metastatic disease. Human prostate adenocarcinoma has a mature luminal phenotype characterized by cytokeratin 8 (CK8) and androgen receptor (AR) expression and prostate-specific antigen (PSA) production. Progressive prostate cancer is almost always treated with androgen deprivation therapy; however, despite such treatment, approximately 10% of prostate cancers progress to metastatic disease.1 Defining mechanisms of resistance to androgen deprivation and progression to metastasis would be significantly aided by the availability of genetically defined models of prostate cancer progression.One of the most common genetic alterations in prostate cancer is deletion of at least one copy of the PTEN tumor suppressor, which occurs in approximately 70% of human prostate cancers. Biallelic deletion of PTEN and the associated increase in AKT phosphorylation, which occurs in roughly 25% of prostate cancers, is correlated with resistance to androgen deprivation therapy.2 A recent genomic profiling study of mostly primary prostate cancers demonstrated that 24% of cases had either a heterozygous or homozygous copy number loss of TP53.3 Other large-scale studies using combined immunohistochemistry (IHC) and sequencing approaches have shown that TP53 mutations occur in approximately 5% of primary tumors and at much higher frequencies in lymph node metastases (16%) and castrate-resistant (26%) tumors. 4,5 In addition, TP53 mutations were found to be independent predictors of tumor recurrence in low-and intermediate-grade cancers. Thus, loss of PTEN and aberrations of TP53 are implicated in aggressive forms of human prostate cancer.

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.