The role of the Mediator complex subunits MED12 and MED15 in the development of androgen-dependent prostate cancer into androgen-independent castration resistant prostate cancer

• Applicant: Professor Dr. Sven Perner
• Subject Area: Pathology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268940839

Hormone sensitive prostate cancer (PCa) is commonly treated with androgen deprivation therapy (ADT), but most tumors relapse resulting in a castration-resistant prostate cancer (CRPC) with poor prognosis. These tumors regain the ability to progress under androgen deprived conditions through ADT-driven molecular alterations. Activation of androgen receptor (AR) signaling and hyper-activation of alternative signaling pathways bypassing the AR are potential molecular changes in metastatic PCa cells. Gene expression profiling of cancer tissues and cell lines untraveled changes in gene expression pattern during androgen ablation, in which resistant tumor cells exhibit a reactivation of the androgen regulated program. AR activity and other signaling pathways are critically dependent upon interactions with co-regulatory proteins and complexes. The Mediator complex is an important co-activator for a broad range of regulatory transcriptional factors including AR. In previous studies, we reported that the involvement of the Mediator complex subunits MED12 and MED15 in PCa progression to CRPC and their direct implication in TGFß signaling. Based on our data so far, we hypothesize that MED12 and MED15 are directly implicated in the development of androgen-dependent PCa into androgen-independent CRPC. We propose proving this hypothesis by pursuing three specific aims. Firstly, we will investigate whether MED12 and MED15 effect the gene expression changes of androgen dependent prostate cancer cells in response to androgen ablation performing Illumina gene chip analysis. Secondly, we will investigate if MED12 and MED15 influence the ability of androgen dependent PCa cells to survive and proliferate under androgen deprived conditions rendering them resistant to androgen deprivation. Thirdly, we will determine the signaling pathway(s) through which MED12 and MED15 may affect the development of drug resistance in androgen dependent PCa cells. Upon the completion of the above aims, we will have evidence whether MED12 or MED15 may serve as predictive markers for development of drug resistance in PCa. Therefore, our results may lead to recommend the targeting of MED12 or MED15 as this may disrupt key signaling pathways which enable cancer cells to survive during androgen deprivation therapy. Thus, this may call for MED12 or MED15 to be established as therapeutic targets in PCa patients harboring high expression levels of MED12 or MED15.

• DFG Programme: Research Grants