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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Cellular Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1404804

Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes

Provisionally accepted
Marija Gjorgoska Marija Gjorgoska 1Lea Šturm Lea Šturm 2Tea Lanisnik Rizner Tea Lanisnik Rizner 2*
  • 1 Institute of Biochemistry, Medical Faculty, University of Ljubljana, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
  • 2 Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

The final, formatted version of the article will be published soon.

    Background: Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time.We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets.We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low-and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression to correlate with lower recurrence in TP53-wt tumors.The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.

    Keywords: endometrial cancer, 11-oxyandrogens, intracrinology, androgen receptor, LC-MS/MS profiling

    Received: 21 Mar 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Gjorgoska, Šturm and Lanisnik Rizner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Tea Lanisnik Rizner, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, SI1000, Slovenia

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