Estrogen receptor-β expression and pharmacological targeting in bladder cancer

Kauffman,Eric  C.; Robinson,Brian  D.; Downes,Martin; Marcinkiewicz,Katarzyna; Vourganti,Srinivas; Scherr,Douglas  S.; Gudas,Lorraine  J.; Mongan,Nigel   P.

doi:10.3892/or.2013.2416

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

Authors:
- Eric C. Kauffman
- Brian D. Robinson
- Martin Downes
- Katarzyna Marcinkiewicz
- Srinivas Vourganti
- Douglas S. Scherr
- Lorraine J. Gudas
- Nigel P. Mongan
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Affiliations: Department of Urology, Weill Cornell Medical College, New York, NY 10065, USA, Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK, Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA, Urologic Oncology Branch, National Cancer Institute of the National Institutes of Health, Bethesda, MD 20892, USA
Published online on: April 23, 2013 https://doi.org/10.3892/or.2013.2416
Pages: 131-138

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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 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.

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