Unifying Theory of Prostate Cancer

摘要

The purpose of this project is to determine the biological basis of the many unique features of prostate cancer, including high incidence, multifocal origin, zonal specificity, and resistance to chemotherapy. We proposed that these characteristics are the result of dysregulated, albeit wild- type, p53 in prostatic epithelial cells. We determined that p53 is not induced in cells derived from either the central zone (resistant to cancer) or the peripheral zone (high frequency of cancer) in response to ionizing radiation. Since the frequency of premalignant lesions is equivalent in these zones, this finding suggests that genomic instability resulting from dysfunctional p53 predisposses both zones to cancer, but that development of invasive cancer in the central zone is limited by unknown factors. We also determined that p53 is not irreversibly nonfunctional in prostatic cells. Inhibition of RNA transcription or of nuclear export led to increased levels of p53 and increased levels of its transcriptional targets, p2l and mdm2. Therefore, mechanisms responsible for upregulation and activation of p53 protein are intact in prostatic epithelial cells. The deficiency, then, apparently lies in the inability of these cells to respond to signals sent by certain DNA-damaging agents, such as ionizing radiation. We recently found that ultraviolet irradiation, in contrast to ionizing radiation, upregulates and activates p53. This finding demonstrates that the pathway leading to induction of p53 is in fact intact in prostatic epithelial cells, but is not triggered by ionizing radiation. Determining the molecular pathways by which these cells recognize and respond to DNA damage will be extremely relevant to prevention of prostate cancer as well as to treatment.