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