Estrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferation


Estrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients'blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ER alpha and ER beta expression in UGS-related BlaCa (n = 27), UGS-related non-malignant lesions (n = 35), and noninfected BlaCa (n = 80). We investigated the potential of ER alpha to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ER alpha modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ER alpha was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ER alpha expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ER alpha expression correlated with presence of schistosome eggs. ERA was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ER alpha active state than 17A-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ER alpha activation promotes proliferation in ER alpha expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ER alpha during UGS and UGS-induced carcinogenesis. (C) 2020 Elsevier Inc. All rights reserved.




Oncology; Urology & Nephrology


Bernardo, C; Santos, J; Costa, C; Tavares, A; Amaro, T; Marques, I; Gouveia, MJ; Felix, V; Afreixo, V; Brindley, PJ; Costa, JM; Amado, F; Helguero, L; Santos, LL



PJB acknowledges support from award R01CA164719 from the National Cancer Institute (NCI), National Institutes of Health (NIH), USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Image acquisition was performed at the LiM facility of iBiMED, a node of PPBI (Portuguese Platform of BioImaging): POCI-01-0145FEDER-022122. The authors wish to thank Dr. Nuno Vale, who in collaboration with others, identified estrogen-related metabolites in urine from patients with UGS. Dr. Vale published his work independently and we have used the publicly available information in that paper as the basis for the MD simulations shown herein. Dr. Vale~s work has been appropriately cited.

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