Promotion of Bladder Cancer Development and Progression by Androgen Receptor Signals
Top Cited Papers
Open Access
- 3 April 2007
- journal article
- research article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 99 (7), 558-568
- https://doi.org/10.1093/jnci/djk113
Abstract
Males have a higher incidence of bladder cancer than females, but the reason remains unknown. Unlike prostate cancer, human bladder cancer is not generally considered to be dependent on hormone activity. We investigated the possible involvement of androgens and the androgen receptor (AR) in bladder cancer. We used N -butyl- N -(4-hydroxybutyl)nitrosamine (BBN) to induce bladder cancer in wild-type male and female mice, with and without castration in males, and in AR knockout (ARKO) male and female mice, with and without dihydrotestosterone (DHT) supplementation in males. We also treated human bladder cancer cell lines, including TCC-SUP and UMUC3, and mouse xenograft models established from these same lines with androgen deprivation therapy (antiandrogen treatment or castration), AR–small-interfering RNA (AR-siRNA), or the anti-AR molecule ASC-J9, which causes selective degradation of the AR. More than 92% of wild-type male and 42% of wild-type female mice treated with BBN eventually developed bladder cancer, whereas none of the male or female ARKO mice did. Treatment with BBN induced bladder cancer in 25% of ARKO mice supplemented with DHT and in 50% of castrated wild-type male mice. Androgen deprivation of AR-positive human bladder cancer cells by androgen depletion in vitro or castration in mice and/or by treatment with the antiandrogen flutamide in vitro or in vivo, as well as AR knockdown by AR-siRNA or by ASC-J9, suppressed cell proliferation in vitro and xenograft tumor growth in vivo. Our findings implicate the involvement of both androgens and the AR in bladder cancer. Targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for bladder cancer.Keywords
This publication has 30 references indexed in Scilit:
- Cancer Statistics, 2006CA: A Cancer Journal for Clinicians, 2006
- A comparative study of the sub-chronic toxic effects of three organic arsenical compounds on the urothelium in F344 rats; gender-based differences in responseToxicology and Applied Pharmacology, 2006
- Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancerUrology, 2004
- Androgen Receptor in Prostate CancerEndocrine Reviews, 2004
- CO-LOCALIZATION OF ANDROGEN RECEPTOR WITH ESTROGEN RECEPTOR β IN THE LOWER URINARY TRACT OF THE MALE RATJournal of Urology, 2001
- Androgen regulation of CYP4B1 responsible for mutagenic activation of bladder carcinogens in the rat bladder: detection of CYP4B1 mRNA by competitive reverse transcription-polymerase chain reactionCancer Letters, 2001
- Promoting Effects and Mechanisms of Action of Androgen in Bladder Carcinogenesis in Male RatsEuropean Urology, 1997
- Cancer risks from arsenic in drinking water.Environmental Health Perspectives, 1992
- Molecular Cloning of Human and Rat Complementary DNA Encoding Androgen ReceptorsScience, 1988
- Specific induction of bladder cancer in mice by butyl-(4-hydroxybutyl)-nitrosamine and the effects of hormonal modifications on the sex difference in responseEuropean Journal of Cancer (1965), 1972