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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-08-0205v1 16/2/325    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by D'Antonio, J. M Articles by Isaacs, J. T Search for Related Content PubMed PubMed Citation Articles by D'Antonio, J. M Articles by Isaacs, J. T

¹ Department of Urology, Brady Urologic Institute
² Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Room 1M43, 1650 Orleans Street, Baltimore, Maryland 21231, USA

(Correspondence should be addressed to J T Isaacs; Email: isaacjo{at}jhmi.edu)

During middle G₁ of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.