Estrogen receptor-β expression and pharmacological targeting in bladder cancer.

TitleEstrogen receptor-β expression and pharmacological targeting in bladder cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsKauffman EC, Robinson BD, Downes M, Marcinkiewicz K, Vourganti S, Scherr DS, Gudas LJ, Mongan NP
JournalOncol Rep
Date Published2013 Jul
KeywordsAdult, Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal, Cell Line, Tumor, Cell Proliferation, Cystectomy, Disease-Free Survival, Estrogen Receptor beta, Estrogens, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local, Nitriles, Propionates, Signal Transduction, Survival, Tamoxifen, Urinary Bladder Neoplasms, Urothelium

A role for estrogen signaling in urothelial carcinoma of the bladder (UCB) is suggested to be associated with more advanced disease with worse outcomes in women. Estrogen receptor β (ERβ) is the predominant receptor in bladder tissues. We aimed to ascertain whether ERβ correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ERβ was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ERβ expression was tested for statistical association with clinicopathological variables and patient survival. ERβ expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ERβ agonist diarylpropionitrile on cell growth were determined. The ERβ level was significantly higher in malignant vs. benign urothelium (P<0.001) and was strongly associated with aggressive tumor histology characterized by lymphovascular (P=0.008) and perineural (P=0.006) invasion, and clinical histories of pelvic irradiation (P=0.005), hydronephrosis (P=0.022) and no intravesical chemotherapy (P=0.038). All patients with a high (>70%) percentage of ERβ positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ERβ level was predictive of worse recurrence-free and overall survival following cystectomy, after adjustment for tumor stage, and remained significantly associated with recurrence-free survival in the multivariable analysis including tumor stage, nodal stage and lymphovascular invasion. Activation of ERβ in bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ERβ in aggressive UCB. Pharmacological targeting of ERβ warrants further investigation as a therapeutic strategy in UCB.

Alternate JournalOncol. Rep.
PubMed ID23612777
PubMed Central IDPMC3729232
Grant ListT32 GM073546 / GM / NIGMS NIH HHS / United States