Prostate cancers of all stages are exquisitely dependent on the activity of the androgen receptor (AR). Ablation of AR activity is the first line of treatment for non-organ confined tumors; however, recurrent, castration resistant tumors (CRPC) ultimately emerge for which no effective therapy has been identified. CRPC arises as a result of resurgent, often ligand-independent AR activity and resumption of AR-dependent cell cycle progression despite sustained castration therapy. Strikingly, there is currently no durable mechanism to treat CRPC. Thus, it is imperative to discern the mechanisms by which AR is controlled and promotes aggressive tumor phenotypes in advanced disease.Recent findings suggest that crosstalk between AR and the cell cycle machinery plays a major role in disease progression:

First, genome-wide analyses revealed that AR exhibits cell cycle stage specific binding events and concomitant transcriptional regulatory functions, consistent with the findings that a subset of cell cycle regulators serve as effectors of AR activity. The underlying basis for and consequence of cell-cycle specific AR function is under investigation, and preliminary findings will be presented.

Second, selected tumor-associated perturbations of the cell cycle machinery appear to differentially reprogram AR activity. Mediated by the ability of RB to suppress AR expression, loss of RB function and/or gain of E2F1 promotes enhanced AR expression that is sufficient to drive expression of CRPC-specific AR activity in vivo. Conversely, alterations in the cyclin D1 pathway promote AR-dependent metastatic phenotypes. Alternative splicing of the CCND1 pre-mRNA in prostate cancer results in upregulation of a highly oncogenic variant, cyclin D1b, that promotes alternative AR signaling. Modeling cyclin D1b and investigation of the consequence for AR activity strikingly revealed that cyclin D1b induces AR-dependent expression of genes associated with epithelial-to-mesenchymal transition (EMT) and metastasis. Mechanistic investigation revealed that cyclin D1b facilitates binding of AR to the SNAI2 regulatory locus and resultant upregulation of Slug expression.
These cyclin D1b-dependent AR functions resulted in acquisition of anchorage-independent growth and in vitro migratory phenotypes.

Third, concordant with in vitro analyses, perturbations in AR-cell cycle crosstalk were found to result in aggressive tumor phenotypes in vivo, and clinical investigation supports alterations in the RB and D-cyclin pathways as promoting transition to castration-resistance and metastatsis, respectively.

Combined, these findings identify perturbations cancer-associated alterations of the cell cycle as major effectors of aberrant AR expression and activity that promote aggressive tumor phenotypes and progression to advanced disease. Ongoing studies are directed at achievable means to target the AR-cell cycle in prostate cancer.