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

Gjorgoska, Marija (author), Šturm, Lea (author), Lanišnik-Rižner, Tea (author)

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. Methods: 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. Results: 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 correlated with lower recurrence in TP53-wt tumors. Conclusions: 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.

• Language: English
• Keywords: endometrial cancer, 11-oxyandrogens, intracrinology, androgen receptor, LC-MS/MS profiling, in vitro models
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 12 str.
• Numbering: Vol. 15, art. 1404804
• PID: 20.500.12556/RUL-166840
• UDC: 616-006:577.2
• ISSN on article: 1664-2392
• DOI: 10.3389/fendo.2024.1404804
• COBISS.SI-ID: 203016707
• Publication date in RUL: 27.01.2025

Record is a part of a journal

• Title: Frontiers in endocrinology
• Publisher: Frontiers Research Foundation
• ISSN: 1664-2392
• COBISS.SI-ID: 3340154

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: endometrijske novotvorbe, 11-oksiandrogeni, intrakrinologija, androgeni receptor, LC-MS/MS profiliranje

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: J3-2535
• Name: Vloga androgenov pri hormonsko odvisnih boleznih: pomen za diagnostiko in zdravljenje

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0449
• Name: Translacijska molekularna endokrinologija za zdravje žensk