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

Abstract

The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-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 17β-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 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-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 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-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 17β-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, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: Gonda Fj Konings, Karlijn Mc Cornel, Sofia Xanthoulea, Bert Delvoux, Margaretha A Skowron, Loes Kooreman, Pasi Koskimies, Camilla Krakstad, Helga B Salvesen, Kim van Kuijk, Yannick Jm Schrooders, Marc Vooijs, Arjan J Groot, Marlies Y Bongers, Roy Fpm Kruitwagen, ENITEC, Andrea Romano
• Journal: The Journal of pathology (J Pathol) Vol. 244 Issue 2 Pg. 203-214 (02 2018) ISSN: 1096-9896 [Electronic] England
• PMID: 29144553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Antineoplastic Agents
• Cyclin A
• Enzyme Inhibitors
• Estrone
• Estradiol
• Estradiol Dehydrogenases
• HSD17B1 protein, human

Topics

• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chick Embryo
• Cyclin A (metabolism)
• Endometrial Neoplasms (drug therapy, enzymology, genetics, pathology)
• Enzyme Inhibitors (pharmacology)
• Estradiol (metabolism, pharmacology)
• Estradiol Dehydrogenases (antagonists & inhibitors, genetics, metabolism)
• Estrone (metabolism, pharmacology)
• Female
• Humans
• Middle Aged
• Molecular Targeted Therapy
• Signal Transduction (drug effects)