20.500.12556/RUL-166840 Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes 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. endometrial cancer 11-oxyandrogens intracrinology androgen receptor LC-MS/MS profiling in vitro models endometrijske novotvorbe 11-oksiandrogeni intrakrinologija androgeni receptor LC-MS/MS profiliranje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-01-27 13:54:39 2025-01-27 13:54:45 2025-01-28 04:00:21 0000-00-00 00:00:00 2024 0 0 12 str. art. 1404804 Vol. 15 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-006:577.2 1664-2392 10.3389/fendo.2024.1404804 203016707 fendo-15-1404804.pdf fendo-15-1404804.pdf 1 45F269043B7B347DB5877DB367141848 3eb7299723837037d452f45173a91c8445a2a84f12b9c603936a417a393b446d 55db1f80-dcae-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=198773 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1404804/full 0 7eeb811b-dcae-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=198774 Medicinska fakulteta 0 0 0