AR, cell cycle, and DDR: Mechanisms and impact on cancer progression
Prostate cancer is the most frequently diagnosed non-cutaneous malignancy and second leading cause of death by cancer in men in the developed world. The development, maintenance, and progression of prostate cancer is dependent upon signaling of the androgen receptor, a ligand-dependent transcription factor. As such, this signaling axis is the target of therapy for high-risk localized and disseminated disease. This strategy is generally effective; however efficacy is transient, as patients relapse in a median of 2-3 years, at which time the disease is resistant to this targeted strategy and termed castration-resistant prostate cancer. As such, understanding the mechanism(s) underpinning androgen receptor signaling is of great importance. Studies described herein will define ways in which androgen receptor signaling and cell cycle machinery crosstalk (Cyclin D1), the means to sensitize prostate cancer cells to genotoxic stress (mTOR inhibition), and convergence of DNA damage response machinery (PARP-1) on androgen receptor signaling. All three of these themes will be discussed with an eye to translational research, and in the context of novel strategies to manage prostate cancer. The methods used to derive the data discussed herein include cell culture systems, xenograft models, and a novel tumor explant protocol. These model systems have been interrogated using biochemical, molecular biological, histological, and pathological assays. From the studies that will be described herein, it will be concluded that targeting both cell cycle-androgen receptor crosstalk, as well as components of the DNA damage response machinery in the context of prostate cancer, yield new insights into the mechanisms of androgen receptor function, and provide rationale for novel means to manage prostate cancer therapy.
Schiewer, Matthew J, "AR, cell cycle, and DDR: Mechanisms and impact on cancer progression" (2012). ETD Collection for Thomas Jefferson University. AAI3539165.