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.

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

“…Preclinical studies on 17βHSD1 inhibitors showed promising results in a mouse model of endometrial hyperplasia (Saloniemi et al, 2010 ;Järvensivu et al, 2015 ) and in various models of EC (Konings et al, 2018 ).…”

Lepidiline A Improves the Balance of Endogenous Sex Hormones and Increases Fecundity by Targeting HSD17B1

“…[ 32 ] We are currently noting an increasing number of studies on HSD17B1 inhibitors for the treatment of hormone‐dependent diseases, including endometriosis, breast cancers, and cervical cancer. [ 33–35 ] Most of the aforementioned hormone‐dependent diseases are associated with HSD17B1 overexpression, and inhibitors are being designed to compete for the active sites on the substrate or coenzyme. [ 36 ] Our competitive assays herein, however, did not show that LA acted on a region of the coenzyme or substrate.…”

Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure

“…However, recent clinical trials indicate that the efficacy of hormonal drugs is improved if combined with other targeted treatments (see Section 3 ) [ 7 ]. Since ongoing pre-clinical research has already identified a number of additional novel endocrine targets [ 8 , 9 , 10 ], it can be envisaged that in the near future several endocrine targets and novel drugs will be available for various combinational regimens in EC clinical trials.…”

“…In the case of EC, pre-clinical models are based on in vitro 2D monolayer cell cultures, 3D spheroid cell cultures, and in vivo models using the chorioallantoic membrane assay (CAM) or by a subcutaneous injection of human EC cell lines in athymic mice. However, these models are suboptimal and often lack estrogen dependency and clear estrogen responses (see Section 3 ) [ 10 , 11 , 12 ].…”