Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G 0 /G 1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

The mechanisms by which Myc overexpression or Pten loss promotes prostate cancer development are poorly understood. We identified the chromatin remodeling protein, ING4, as a crucial switch downstream of Myc and Pten that is required for human prostate epithelial differentiation. Myc-induced transient expression of ING4 is required for the differentiation of basal epithelial cells into luminal cells, while sustained ING4 expression induces apoptosis. ING4 expression is lost in >60% of human primary prostate tumors. ING4 or Pten loss prevents epithelial cell differentiation, which was necessary for tumorigenesis. Pten loss prevents differentiation by blocking ING4 expression, which is rescued by ING4 re-expression. Pten or ING4 loss generates tumor cells that co-express basal and luminal markers, indicating prostate oncogenesis occurs through disruption of an intermediate step in the prostate epithelial differentiation program. Thus, we identified a new epithelial cell differentiation switch involving Myc, Pten and ING4, which when disrupted leads to prostate tumorigenesis. Myc overexpression and Pten loss are common genetic abnormalities in prostate cancer, whereas loss of the tumor suppressor ING4 has not been reported. This is the first demonstration that transient ING4 expression is absolutely required for epithelial differentiation, its expression is dependent on Myc and Pten, and it is lost in the majority of human prostate cancers. This is the first demonstration that loss of ING4, either directly or indirectly through loss of Pten, promotes Myc-driven oncogenesis by deregulating differentiation. The clinical implication is that Pten/ING4 negative and ING4-only negative tumors may reflect two distinct subtypes of prostate cancer.

Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes ( ERG, PTEN, and SPOP) are recurrently mutated in more than 10% of primary tumors. On the other hand, metastatic castration-resistant tumors have more mutations, but, with the exception of the androgen receptor gene ( AR), no single gene is altered in more than half of tumors. Structural genomic rearrangements are common, including ERG fusions, copy gains involving the MYC locus, and copy losses containing PTEN. Overall, instead of being associated with a single dominant driver event, prostate tumors display various combinations of modifications in oncogenes and tumor suppressors. This review takes a broad look at the recent advances in PCa research, including understanding the genetic alterations that drive the disease and how specific mutations can sensitize tumors to potential therapies. We begin with an overview of the genomic landscape of primary and metastatic PCa, enabled by recent large-scale sequencing efforts. Advances in three-dimensional cell culture techniques and mouse models for PCa are also discussed, and particular emphasis is placed on the benefits of patient-derived xenograft models. We also review research into understanding how ETS fusions (in particular, TMPRSS2-ERG) and SPOP mutations contribute to tumor initiation. Next, we examine the recent findings on the prevalence of germline DNA repair mutations in about 12% of patients with metastatic disease and their potential benefit from the use of poly(ADP-ribose) polymerase (PARP) inhibitors and immune modulation. Lastly, we discuss the recent increased prevalence of AR-negative tumors (neuroendocrine and double-negative) and the current state of immunotherapy in PCa. AR remains the primary clinical target for PCa therapies; however, it does not act alone, and better understanding of supporting mutations may help guide the development of novel therapeutic strategies.