Pharmacological inhibition of 17 beta-hydroxysteroid dehydrogenase impairs human endometrial cancer growth in an orthotopic xenograft mouse model

Sofia Xanthoulea*, Gonda F. J. Konings, Niina Saarinen, Bert Delvoux, Loes F. S. Kooreman, Pasi Koskimies, Merja R. Hakkinen, Seppo Auriola, Elisabetta D'Avanzo, Youssef Walid, Frank Verhaegen, Natasja G. Lieuwes, Florian Caiment, Roy Kruitwagen, Andrea Romano, ENITEC

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)


Endometrial cancer (EC) is the most common gynaecological tumor in developed countries and its incidence is increasing. Approximately 80% of newly diagnosed EC cases are estrogen-dependent. Type 1 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD-1) is the enzyme that catalyzes the final step in estrogen biosynthesis by reducing the weak estrogen estrone (E1) to the potent estrogen 17 beta-estradiol (E2), and previous studies showed that this enzyme is implicated in the intratumoral E2 generation in EC. In the present study we employed a recently developed orthotopic and estrogen-dependent xenograft mouse model of EC to show that pharmacological inhibition of the 17 beta-HSD-1 enzyme inhibits disease development. Tumors were induced in one uterine horn of athymic nude mice by intrauterine injection of the well-differentiated human endometrial adenocarcinoma Ishikawa cell line, modified to express human 17 beta-HSD-1 in levels comparable to EC, and the luciferase and green fluorescent protein reporter genes. Controlled estrogen exposure in ovariectomized mice was achieved using subcutaneous MedRod implants that released either the low active estrone (E1) precursor or vehicle. A subgroup of E1 supplemented mice received daily oral gavage of FP4643, a well-characterized 17 beta-HSD-1 inhibitor. Bioluminescence imaging (BLI) was used to measure tumor growth non-invasively. At sacrifice, mice receiving E1 and treated with the FP4643 inhibitor showed a significant reduction in tumor growth by approximately 65% compared to mice receiving E1. Tumors exhibited metastatic spread to the peritoneum, to the lymphovascular space (LVI), and to the thoracic cavity. Metastatic spread and LVI invasion were both significantly reduced in the inhibitor-treated group. Transcriptional profiling of tumors indicated that FP4643 treatment reduced the oncogenic potential at the mRNA level. In conclusion, we show that 17 beta-HSD-1 inhibition represents a promising novel endocrine treatment for EC.

Original languageEnglish
Pages (from-to)18-29
Number of pages12
JournalCancer Letters
Publication statusPublished - 28 Jun 2021


  • 17 beta-estradiol
  • FP4643
  • 17 beta-HSD-1 inhibitor
  • Ishikawa
  • Bioluminescence imaging
  • TYPE-1
  • CELL
  • MICE

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