A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 11; pp. 4315 - 4319
• Main Authors: GREGORY, Christopher W, HE, Bin, JOHNSON, Raymond T, FORD, O. Harris, MOHLER, James L, FRENCH, Frank S, WILSON, Elizabeth M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2001
• Subjects: Aged; Androgen Antagonists - therapeutic use; androgen depravation therapy; Animals; Biological and medical sciences; Dihydrotestosterone - pharmacology; Histone Acetyltransferases; Humans; Male; Medical sciences; 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; Nephrology. Urinary tract diseases; Nuclear Receptor Coactivator 1; Nuclear Receptor Coactivator 2; Orchiectomy; prostate carcinoma; 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; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Hormonodependence; Nuclear receptor; Relapse; Urinary system disease; Prostate disease; Androgen; Pathogenesis; Hyperplasia; Tumoral tissue; Male; Activation; Malignant tumor; In vitro; Transcription factor; Sex steroid hormone; Mechanism of action; Male genital diseases; Prostate; Transcription factor TIF2; Hormonal receptor
• ISSN: 0008-5472; 1538-7445

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.