Androgen Receptor and Cell Cycle Interplay in Cancer: Mechanisms and Implications
Prostate cancer (PCa) remains the most highly diagnosed, noncutaneous malignancy in men in the United States, and is the third leading cause of mortality within this category. As PCa is typically reliant on signaling of the ligand dependent transcription factor the androgen receptor (AR) throughout all stages of disease, PCa treatment targets the AR signaling axis. However, while these therapies are initially effective, patients typically relapse in 36-48 months and progress to the ultimately fatal stage of disease, termed castration-resistant prostate cancer (CRPC), for which there remains no cure. As such, defining both the molecular mechanisms underlying AR signaling and the associated networks that contribute to PCa maintenance and progression is vital. Studies herein describe AR activity in proliferating cells as a function of cell cycle phase, illuminating expanded AR binding and identifying a novel, cell cycle specific AR target associated with development of metastases and lethal disease. Additionally, data in the present study validate loss of the cell cycle regulator retinoblastoma protein (RB) as the major mechanism of RB pathway disruption in CRPC. Further, studies here nominate expansion of E2F Transcription Factor 1 (E2F1) activity as the underlying molecular mechanism of RB loss-driven CRPC, as determined through genome-wide interrogation of cell culture systems and in vivo tumor samples. Utilizing data herein, it will be concluded that cross-talk between the cell cycle machinery and PCa signaling axes drive advanced PCa phenotypes, mediated through expanded activity of transcriptional regulators and novel gene networks that drive late stage disease.
Biology|Molecular biology|Cellular biology
McNair, Christopher M, "Androgen Receptor and Cell Cycle Interplay in Cancer: Mechanisms and Implications" (2017). ETD Collection for Thomas Jefferson University. AAI10282362.