Blocking 17 beta-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Gonda F. J. Konings, Karlijn M. C. Cornel, Sofia Xanthoulea, Bert Delvoux, Margaretha A. Skowron, Loes Kooreman, Pasi Koskimies, Camilla Krakstad, Helga B. Salvesen, Kim van Kuijk, Yannick J. M. Schrooders, Marc Vooijs, Arjan J. Groot, Marlies Y. Bongers, Roy F. P. M. Kruitwagen, Andrea Romano*, ENITEC

*Corresponding author for this work

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Abstract

The enzyme type 1 17 beta -hydroxysteroid dehydrogenase (17 beta-HSD-1), responsible for generating active 17 beta-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17 beta-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17 beta-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17 beta-HSD-1 activity could be blocked by a specific 17 beta-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17 beta-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17 beta-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17 beta-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17 beta-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17 beta-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17 beta-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17 beta-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17 beta-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Original languageEnglish
Pages (from-to)203-214
Number of pages12
JournalJournal of Pathology
Volume244
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • 17 beta-hydroxysteroid dehydrogenase type 1
  • endometrial cancer
  • estrone
  • 17 beta-estradiol
  • estrogen metabolism
  • STEROID SULFATASE
  • CHORIOALLANTOIC MEMBRANE
  • ESTROGEN BIOSYNTHESIS
  • PHASE-II
  • IN-VIVO
  • CARCINOMA
  • INHIBITORS
  • EXPRESSION
  • 17-BETA-ESTRADIOL
  • METABOLISM

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