Promotion of bladder cancer development and progression by androgen receptor signals

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)558-568
Number of pages11
JournalJournal of the National Cancer Institute
Volume99
Issue number7
DOIs
Publication statusPublished - Apr 4 2007
Externally publishedYes

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Androgen Receptors
Urinary Bladder Neoplasms
Androgens
Androgen Antagonists
Dihydrotestosterone
Castration
Heterografts
Knockout Mice
Small Interfering RNA
Butylhydroxybutylnitrosamine
Flutamide
Orchiectomy
Prostatic Neoplasms
Cell Proliferation
Hormones
Cell Line
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Miyamoto, H., Yang, Z., Chen, Y. T., Ishiguro, H., Uemura, H., Kubota, Y., ... Chang, C. (2007). Promotion of bladder cancer development and progression by androgen receptor signals. Journal of the National Cancer Institute, 99(7), 558-568. https://doi.org/10.1093/jnci/djk113

Promotion of bladder cancer development and progression by androgen receptor signals. / Miyamoto, Hiroshi; Yang, Zhiming; Chen, Yei Tsung; Ishiguro, Hitoshi; Uemura, Hiroji; Kubota, Yoshinobu; Nagashima, Yoji; Chang, Yu Jia; Hu, Yueh Chiang; Tsai, Meng Yin; Yeh, Shuyuan; Messing, Edward M.; Chang, Chawnshang.

In: Journal of the National Cancer Institute, Vol. 99, No. 7, 04.04.2007, p. 558-568.

Research output: Contribution to journalArticle

Miyamoto, H, Yang, Z, Chen, YT, Ishiguro, H, Uemura, H, Kubota, Y, Nagashima, Y, Chang, YJ, Hu, YC, Tsai, MY, Yeh, S, Messing, EM & Chang, C 2007, 'Promotion of bladder cancer development and progression by androgen receptor signals', Journal of the National Cancer Institute, vol. 99, no. 7, pp. 558-568. https://doi.org/10.1093/jnci/djk113
Miyamoto, Hiroshi ; Yang, Zhiming ; Chen, Yei Tsung ; Ishiguro, Hitoshi ; Uemura, Hiroji ; Kubota, Yoshinobu ; Nagashima, Yoji ; Chang, Yu Jia ; Hu, Yueh Chiang ; Tsai, Meng Yin ; Yeh, Shuyuan ; Messing, Edward M. ; Chang, Chawnshang. / Promotion of bladder cancer development and progression by androgen receptor signals. In: Journal of the National Cancer Institute. 2007 ; Vol. 99, No. 7. pp. 558-568.
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abstract = "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.",
author = "Hiroshi Miyamoto and Zhiming Yang and Chen, {Yei Tsung} and Hitoshi Ishiguro and Hiroji Uemura and Yoshinobu Kubota and Yoji Nagashima and Chang, {Yu Jia} and Hu, {Yueh Chiang} and Tsai, {Meng Yin} and Shuyuan Yeh and Messing, {Edward M.} and Chawnshang Chang",
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AU - Yang, Zhiming

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AU - Ishiguro, Hitoshi

AU - Uemura, Hiroji

AU - Kubota, Yoshinobu

AU - Nagashima, Yoji

AU - Chang, Yu Jia

AU - Hu, Yueh Chiang

AU - Tsai, Meng Yin

AU - Yeh, Shuyuan

AU - Messing, Edward M.

AU - Chang, Chawnshang

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N2 - 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.

AB - 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.

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