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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303681 | GEO | 2025/07/26

REPOSITORIES: GEO

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Project description:Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2(LoxP/LoxP), abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a signature of mitochondrial dysfunction. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: reduced mitochondrial content and structural disruptions in retained mitochondria. Human LS-ECs also exhibited reduced mitochondrial content compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including decreased oxidative phosphorylation and heightened susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS. To achieve Msh2 loss in the endometrium, we bred progesterone receptor Cre knock-in (PR-Cre) mice to Msh2(LoxP/LoxP) mice to produce PR-Cre+Msh2(LoxP/LoxP) mice with targeted loss of MSH2 expression in tissues that express PR, including the uterus (hereafter abbreviated Msh2KO). Control mice contain Msh2(LoxP/LoxP) without PR-Cre. We profiled Msh2KO endometrial tumors, Msh2KO benign endometrium, and control mouse benign endometrium using transcriptomic profiling of microdissected glands via microarray analysis (ClariomD, Affymetrix).

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

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