Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway

• Published in: Clinical & translational oncology Vol. 11; no. 1; pp. 5 - 10
• Main Authors: Mellado, Begoña, Codony, Jordi, Ribal, María José, Visa, Laura, Gascón, Pere
• Format: Journal Article
• Language: English
• Published: Milan Springer Milan 2009
• Subjects: Androgen Antagonists - therapeutic use; Drug Resistance, Neoplasm - genetics; Educational Series; Humans; Male; Medicine; Medicine & Public Health; Molecular Biology - trends; Oncology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - physiology; Prostate cancer; Androgen-independence; Androgen receptor
• ISSN: 1699-048X; 1699-3055
• DOI: 10.1007/s12094-009-0304-3

Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are a number of novel agents targeting the AR signalling pathway under development, including more effective antiandrogens; inhibitors of CYP17, inhibitors of HSP90, inhibitors of histone deacetylases and inhibitors of tyrosine kinase inhibitors.