TY - JOUR
T1 - Chemoprevention of BBN-induced bladder carcinogenesis by the selective Estrogen receptor modulator tamoxifen
AU - George, Suraj Konnath
AU - Tovar-Sepulveda, Veronica
AU - Shen, Steven
AU - Jian, Weiguo
AU - Zhang, Yiqun
AU - Hilsenbeck, Susan G.
AU - Lerner, Seth P.
AU - Smith, Carolyn L.
N1 - Funding Information:
Address all correspondence to: Carolyn L. Smith, PhD, Molecular and Cellular Biology, BCM130, One Baylor Plaza, Houston, TX 77030. E-mail: carolyns@bcm.tmc.edu 1This work was supported by the Biostatistics and Informatics Core of the National Cancer Institute Cancer Center Support grant (P30CA125123), Public Health Service grant (CA119271), and funds from the Dan L. Duncan Cancer Center and the Partnership for Bladder Cancer Research. Received 2 March 2013; Revised 2 March 2013; Accepted 4 March 2013 Copyright © 2013 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124/13 DOI 10.1593/tlo.13247
PY - 2013
Y1 - 2013
N2 - Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8-20 weeks) or concurrent and subsequent (8-32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5-8 weeks) or after (20-32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
AB - Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8-20 weeks) or concurrent and subsequent (8-32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5-8 weeks) or after (20-32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
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U2 - 10.1593/tlo.13247
DO - 10.1593/tlo.13247
M3 - Article
AN - SCOPUS:84878732666
VL - 6
SP - 244
EP - 255
JO - Translational Oncology
JF - Translational Oncology
SN - 1936-5233
IS - 3
ER -