Abstract
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.
Publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Aged
- Androgen Antagonists / therapeutic use
- Animals
- Dihydrotestosterone / pharmacology
- Histone Acetyltransferases
- Humans
- Male
- Mice
- Mice, Nude
- Middle Aged
- Neoplasm Recurrence, Local / metabolism*
- Neoplasm Recurrence, Local / pathology
- Neoplasms, Hormone-Dependent / metabolism*
- Neoplasms, Hormone-Dependent / pathology
- Neoplasms, Hormone-Dependent / therapy
- Nuclear Receptor Coactivator 1
- Nuclear Receptor Coactivator 2
- Orchiectomy
- Prostatic Hyperplasia / metabolism
- Prostatic Hyperplasia / pathology
- Prostatic Neoplasms / metabolism*
- Prostatic Neoplasms / pathology
- Prostatic Neoplasms / therapy
- Receptors, Androgen / biosynthesis
- Receptors, Androgen / physiology*
- Testosterone / pharmacology
- Transcription Factors / biosynthesis
- Transcription Factors / genetics
- Transcriptional Activation
- Transplantation, Heterologous
Substances
- Androgen Antagonists
- Nuclear Receptor Coactivator 2
- Receptors, Androgen
- Transcription Factors
- Dihydrotestosterone
- Testosterone
- Histone Acetyltransferases
- NCOA1 protein, human
- Ncoa1 protein, mouse
- Nuclear Receptor Coactivator 1