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BACKGROUND. Estrogen receptors (ERs) are known to mediate important physiologic responses as well as the growth of some tumors in response to estradiol stimulation. In a previous study the selective ER modulator raloxifene was shown to induce apoptosis in an ER[beta]-positive bladder cancer cell line. However, the expression of ER[beta] in human bladder cancer has not been thoroughly investigated.

METHODS. ER[alpha] and ER[beta] expression in 224 bladder tumor samples was evaluated using tissue microarray and immunohistochemistry. Levels of ER[alpha] and ER[beta] protein and mRNA expression were determined in several bladder cancer cell lines using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. The effect of estradiol and antiestrogen treatments on RT4 bladder cancer cell growth was determined by cell proliferation assays.

RESULTS. Analyses revealed that only 2 human bladder cancers weakly expressed ER[alpha]. In contrast, the expression of ER[beta] was detected in 141 tumors (63%). ER[beta] was expressed in 58% of WHO Grade 1 and 2 tumors, whereas 70% of Grade 3 tumors demonstrated expression (P=.085). Importantly, although only 53% and 55% of Ta and T1 tumors demonstrated ER[beta] expression, 80% of T2, 81% of T3, and 75% of T4 tumors showed ER[beta] expression. The differences in ER[beta] expression between Ta/T1 and T2/T3/T4 tumors were found to be highly significant (P<.001). Metastatic transitional cell carcinomas had ER[beta] expression (80%) comparable to that of muscle invasive bladder cancers. Western blot analysis detected ER[beta] protein expression in each of the 5 bladder cancer cell lines tested, whereas no or very low levels of ER[alpha] were found. Quantitative RT-PCR revealed that higher levels of ER[beta] than ER[alpha] mRNA were present in 5637, T-24, TSU-Pr1, and TCC-Sup bladder cancer cells, whereas ER-[alpha] mRNA levels were greater than ER[beta] in RT4 cells. Treatment with 17[beta]-estradiol modestly increased RT4 cell growth, whereas the antiestrogens, 4-hydroxtamoxifen, raloxifene, or ICI 182,780 inhibited the growth of RT4 cells.

CONCLUSIONS. ER[beta] is the dominant receptor expressed in bladder cancer cell lines and in the majority of human bladder tumors. Moreover, the degree of ER[beta] expression increases with increasing stage and grade of differentiation. Antiestrogens have an inhibitory effect on the growth of bladder cancer cells in vitro. Cancer 2006. (C) 2006 American Cancer Society.

: Estrogen receptor (ER) [beta] is the dominant ER expressed in bladder cancer cell lines and in the majority of human bladder tumors. Moreover, the degree of ER[beta] expression increases with increasing stage and grade of differentiation. Studies of the effects of pharmacologic agents that positively and negatively regulate ER[beta] function should provide insight into the biologic importance of this receptor in human bladder cancer.

Copyright (C) 2006 John Wiley & Sons, Inc.