AR, the cell cycle, and prostate cancer

Nucl Recept Signal. 2008 Feb 1:6:e001. doi: 10.1621/nrs.06001.

Abstract

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression.

Publication types

  • Review

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use*
  • Androgen Receptor Antagonists*
  • Cell Cycle / drug effects*
  • Cell Cycle / physiology
  • Cell Proliferation / drug effects*
  • Cyclin-Dependent Kinases / metabolism
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Phosphorylation
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism

Substances

  • AR protein, human
  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Receptors, Androgen
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinases
  • Prostate-Specific Antigen