Estrogen receptor-β expression and pharmacological targeting in bladder cancer

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 beta (ER beta) is the predominant receptor in bladder tissues. We aimed to ascertain whether ER beta correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ER beta was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ER beta expression was tested for statistical association with clinicopathological variables and patient survival. ER beta expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ER beta agonist diarylpropionitrile on cell growth were determined. The ER beta 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 ER beta positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ER beta 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 ER beta 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 ER beta in aggressive UCB. Pharmacological targeting of ER beta warrants further investigation as a therapeutic strategy in UCB.