A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy.
The development and growth of prostate cancer depends on the androgen receptor and its high-affinity binding of dihydrotestosterone, which derives from testosterone. Most prostate tumors regress after therapy to prevent testosterone production by the testes, but the tumors eventually recur and cause death. A critical question is whether the androgen receptor mediates recurrent tumor growth after androgen deprivation therapy. Here we report that a majority of recurrent prostate cancers express high levels of the androgen receptor and two nuclear receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. Overexpression of these coactivators increases androgen receptor transactivation at physiological concentrations of adrenal androgen. Furthermore, we provide a molecular basis for this activation and suggest a general mechanism for recurrent prostate cancer growth.
Gregory
C W
CW
Laboratory for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
He
B
B
Johnson
R T
RT
Ford
O H
OH
Mohler
J L
JL
French
F S
FS
Wilson
E M
EM
D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D009919:Orchiectomy; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous
D000726:Androgen Antagonists; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D014157:Transcription Factors; D013196:Dihydrotestosterone; D013739:Testosterone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1