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J Pathol. 2018 Feb;244(2):203-214. doi: 10.1002/path.5004. Epub 2018 Jan 3.

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

Author information

1
GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
2
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, The Netherlands.
3
Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, Germany.
4
Department of Pathology, Maastricht University Medical Centre, The Netherlands.
5
Forendo Pharma Ltd, Turku, Finland.
6
Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway.
7
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.
8
Department of Radiotherapy (MAASTRO), Maastricht University, The Netherlands.

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.

KEYWORDS:

17β-estradiol; 17β-hydroxysteroid dehydrogenase type 1; endometrial cancer; estrogen metabolism; estrone

PMID:
29144553
DOI:
10.1002/path.5004

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