Introduction/Background*Endometrial (EC) and ovarian cancer (OC) are female pathologies that express androgen receptor (AR) to different extents, however, the role of the AR ligands, i.e., androgens and their 11-oxygenated metabolites in EC and OC onset and progression is poorly understood. Active androgens can form from the abundant precursor dehydroepiandrosterone sulfate (DHEA-S) from the adrenal cortex; however, local synthesis and metabolism in endometrial and ovarian cancer tissue may have important roles as well.
Objective To explore the local androgen synthesis and metabolism in EC and OC.
Methodology Gene expression of key enzymes involved in the androgen synthesis and metabolism was examined in model cell lines of type I and II EC, and high grade serous OC. The Cancer Genome Atlas (TCGA) database was searched for the expression of these genes in EC and OC tissues using the UCSC Xena platform.
Result(s)*Our gene expression data indicate that model cell lines of EC and OC can potentially synthesize the potent androgens testosterone (T) and 5α-dihydrotestosterone (5α-DHT) from DHEA-S, as well as the equally potent metabolites 11-keto-T and 11-keto-DHT from the adrenal precursor 11-OH-androstendione. Interestingly, the expression of AKR1C3, encoding an aldo-keto reductase family enzyme that catalyses the formation of T and 11-keto-T, and the expression of SRD5A1, encoding a steroid 5α-reductase that catalyses the conversion of T to 5α-DHT were higher in certain model cell lines of EC and OC comparing to the respective controls. According to the TCGA database, SRD5A1 expression correlates with a worse overall survival in EC, whereas HSD11B2 expression with a positive progression free survival in OC.
Conclusion*Gene expression analysis indicate that active androgens and 11-oxyandrogens can form in EC and OC. Further metabolism studies are in progress. Assessment of the effect of androgens and their metabolites on EC and OC development and determination of their systemic levels may unravel novel therapeutic targets and new diagnostic and prognostic biomarkers.
This work was supported by the Slovenian Research Agency. Grant number: J3-2535.
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