Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway

Cell. 2006 Feb 10;124(3):615-29. doi: 10.1016/j.cell.2005.12.032.


Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Androgen Antagonists / metabolism
  • Androgen Antagonists / pharmacology
  • Animals
  • Cell Communication
  • Cell Line
  • Drug Resistance, Neoplasm
  • Humans
  • In Vitro Techniques
  • Interleukin-1 / pharmacology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Models, Biological
  • Neoplasms, Hormone-Dependent / drug therapy
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / pathology
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Signal Transduction


  • Androgen Antagonists
  • Interleukin-1
  • Receptors, Steroid