2022-RA-1450-ESGO Androgen metabolism and signalling in ovarian cancer

Introduction/Background

Ovarian cancer (OC) is a heterogenous disease with increasing incidence rate. Epidemiological studies associate androgens with OC aetiology, nonetheless, their role, and especially that of their 11-oxygenated metabolites is not clear. Here we explore whether androgen metabolism can take place locally in ovarian tumours and assess the expression of the androgen receptor (AR) in OC tissues.

Methodology

The expression of key enzymes in the androgen metabolism was examined in model cell lines of high-grade serous OC (HGSOC). Next, the profile of androgen metabolites formed from precursors, dehydroepiandrosterone sulphate (DHEA-S) and 11-OH-androstenedione (11-OH-A4) was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The TCGA Pancancer atlas data was used to explore AR expression in OC tissues.

Results

Our gene expression data indicate that in HGSOC cell lines, classical androgen precursors, such as DHEA-S can give rise to potent androgens, such as testosterone (T) and dihydrotestosterone (DHT), however, not to 11-oxyandrogens. Indeed, our metabolism studies showed that HGSOC cell lines metabolize DHEA-S mainly to DHEA and A4. Interestingly, highest T and DHT levels formed in the chemo resistant cell line COV362, which expresses highest AKR1C3 and SRD5A2 levels. Furthermore, HGSOC cell lines metabolized 11-OH-A4 mainly to active androgens 11-K-A4 and 11-K-T. Highest 11-K-T levels were synthesized in Kuramochi, which expresses highest HSD11B2 levels. Notably, AR expression correlated with a better overall survival in HGSOC patients (data from the TCGA Pancancer atlas).

Conclusion

In ovarian tumours, classical androgen precursors give rise to classical bioactive androgens, whereas 11-oxyandrogen precursors to equally potent 11-oxyandrogens. Higher AKR1C3 and SRD5A2 expression contribute to greater T and DHT synthesis, whereas higher HSD11B2 expression to greater 11-K-T levels. AR expression correlates with a better overall survival, suggesting a prognostic potential of androgens and 11-oxyandrogens in OC. Studies of the molecular mechanism of androgen signalling in OC are ongoing.