Promotion of Bladder Cancer Development and Progression by Androgen Receptor Signals
Author: Hiroshi Miyamoto , Zhiming Yang , Yei-Tsung Chen , Hitoshi Ishiguro , Hiroji Uemura , Yoshinobu Kubota , Yoji Nagashima , Yu-Jia Chang , Yueh-Chiang Hu , Meng-Yin Tsai , Shuyuan Yeh , Edward M. Messing , Chawnshang Chang
Journal: J Natl Cancer Inst 2007;99: 558 – 68
Background 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.
Methods 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.
Results 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.
Conclusions 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.
Prior knowledge
The incidence of bladder cancer is higher in males than females. The reason for the difference is unknown, but it is possible that androgens or the androgen receptor are involved in the development of bladder cancer.
Study design
Cell line and mouse model (both xenograft and carcinogen-induced tumors) study.
Proliferation of human bladder cancer cells was reduced both in vitro and in vivo by treatments that reduce androgen activity as well as by treatments that block androgen receptor function. The development of bladder cancer in mice treated with a known bladder carcinogen was reduced in male mice with lowered levels of the androgen receptor or of androgens.
If bladder cancer development or progression is indeed influenced by both androgens and the androgen receptor, then it is possible that bladder cancer could be prevented or treated by targeting these molecules or related signaling pathways.
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