PMID- 32905529 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2156-6976 (Print) IS - 2156-6976 (Electronic) IS - 2156-6976 (Linking) VI - 10 IP - 8 DP - 2020 TI - Estrogen receptor-beta signaling induces cisplatin resistance in bladder cancer. PG - 2523-2534 AB - 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-beta (ERbeta) signals in urothelial cancer progression. In this study, we aimed to investigate whether ERbeta 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 ERbeta 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 ERbeta were significantly more resistant to cisplatin treatment at its pharmacological concentrations, compared with ERbeta knockdown sublines via short hairpin RNA virus infection. An ER modulator tamoxifen increased sensitivity to cisplatin in ERalpha-negative/ERbeta-positive cell lines, while, in an estrogen-depleted condition, 17beta-estradiol reduced it. Additionally, western blot showed considerable elevation in ERbeta 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 ERbeta. The expression and activity of beta-catenin known to involve cisplatin resistance was also up-regulated in cisplatin-resistant cells, which was further induced by 17beta-estradiol treatment. The present results suggest that estrogen-mediated ERbeta signaling plays an important role in modulating cisplatin sensitivity in bladder cancer cells. Targeting ERbeta during chemotherapy may thus be a useful strategy to overcome cisplatin resistance especially in female patients with ERbeta-positive bladder cancer. CI - AJCR Copyright (c) 2020. FAU - Goto, Takuro AU - Goto T AD - Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA. AD - James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY, USA. AD - Department of Urology, Tohoku University Graduate School of Medicine Sendai, Japan. FAU - Kashiwagi, Eiji AU - Kashiwagi E AD - Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD, USA. AD - James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore, MD, USA. FAU - Jiang, Guiyang AU - Jiang G AD - Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA. AD - James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY, USA. FAU - Nagata, Yujiro AU - Nagata Y AD - Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA. AD - James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY, USA. FAU - Teramoto, Yuki AU - Teramoto Y AD - Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA. AD - James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY, USA. FAU - Baras, Alexander S AU - Baras AS AD - Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD, USA. AD - James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore, MD, USA. FAU - Yamashita, Shinichi AU - Yamashita S AD - Department of Urology, Tohoku University Graduate School of Medicine Sendai, Japan. FAU - Ito, Akihiro AU - Ito A AD - Department of Urology, Tohoku University Graduate School of Medicine Sendai, Japan. FAU - Arai, Yoichi AU - Arai Y AD - Department of Urology, Tohoku University Graduate School of Medicine Sendai, Japan. AD - Department of Urology, Miyagi Cancer Center Natori, Japan. FAU - Miyamoto, Hiroshi AU - Miyamoto H AD - Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA. AD - James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY, USA. AD - Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD, USA. AD - James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore, MD, USA. AD - Department of Urology, University of Rochester Medical Center Rochester, NY, USA. LA - eng PT - Journal Article DEP - 20200801 PL - United States TA - Am J Cancer Res JT - American journal of cancer research JID - 101549944 PMC - PMC7471368 OTO - NOTNLM OT - Bladder cancer OT - chemoresistance OT - cisplatin OT - estrogen receptor OT - immunohistochemistry COIS- None. EDAT- 2020/09/10 06:00 MHDA- 2020/09/10 06:01 PMCR- 2020/08/01 CRDT- 2020/09/09 18:15 PHST- 2020/06/23 00:00 [received] PHST- 2020/07/14 00:00 [accepted] PHST- 2020/09/09 18:15 [entrez] PHST- 2020/09/10 06:00 [pubmed] PHST- 2020/09/10 06:01 [medline] PHST- 2020/08/01 00:00 [pmc-release] PST - epublish SO - Am J Cancer Res. 2020 Aug 1;10(8):2523-2534. eCollection 2020.