Estrogen receptor-β expression and pharmacological targeting in bladder cancer

Abstract

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 ߠ(ERߩ is the predominant receptor in bladder tissues. We aimed to ascertain whether ERߠcorrelates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ERߠwas measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ERߠexpression was tested for statistical association with clinicopathological variables and patient survival. ERߠexpression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ERߠagonist diarylpropionitrile on cell growth were determined. The ERߠlevel 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 ERߠpositivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ERߠlevel 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 ERߠin bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ERߠin aggressive UCB. Pharmacological targeting of ERߠwarrants further investigation as a therapeutic strategy in UCB.