The efficacy of
cisplatin-based
chemotherapy in patients with
bladder cancer is often limited due to the development of therapeutic resistance. Our recent findings in
bladder cancer suggested that activation of
prostaglandin receptors (e.g. EP2, EP4) or
cyclooxygenase (COX)-2 induced
cisplatin resistance. Meanwhile, emerging evidence indicates the involvement of
estrogen receptor-β (ERβ) signals in urothelial
cancer progression. In this study, we aimed to investigate whether ERβ activity was associated with
cisplatin sensitivity in
bladder cancer. Immunohistochemistry in muscle-invasive
bladder cancer specimens from 55 patients who had subsequently received at least 3 cycles of
cisplatin +
gemcitabine neoadjuvant chemotherapy showed that ERβ was positive in 38% of responders vs. 71% of non-responders (P = 0.016), including 42% of male responders vs. 65% of male non-responders (P = 0.142) and 20% of female responders vs. 100% of female non-responders (P = 0.048). Then,
cisplatin cytotoxicity was compared in human
bladder cancer cell lines. Control sublines endogenously expressing ERβ were significantly more resistant to
cisplatin treatment at its pharmacological concentrations, compared with ERβ knockdown sublines via
short hairpin RNA virus infection. An ER modulator
tamoxifen increased sensitivity to
cisplatin in ERα-negative/ERβ-positive cell lines, while, in an
estrogen-depleted condition, 17β-estradiol reduced it. Additionally, western blot showed considerable elevation in ERβ expression in
cisplatin-resistant
bladder cancer sublines, compared with respective controls. Moreover, treatment with
tamoxifen or a
COX-2 inhibitor celecoxib increased
cisplatin sensitivity even in resistant cells, while COX-2/EP2/EP4 inhibitor treatment resulted in reduced expression of ERβ. The expression and activity of β-
catenin known to involve
cisplatin resistance was also up-regulated in
cisplatin-resistant cells, which was further induced by 17β-estradiol treatment. The present results suggest that
estrogen-mediated ERβ signaling plays an important role in modulating
cisplatin sensitivity in
bladder cancer cells. Targeting ERβ during
chemotherapy may thus be a useful strategy to overcome
cisplatin resistance especially in female patients with ERβ-positive
bladder cancer.