Endocrine Abstracts

Steroid receptors play essential roles in physiology and disease, including breast and prostate cancer. The interaction between different steroid receptors has been studied extensively at the level of their physical interaction on chromatin. We hypothesized that androgen receptor (AR) and glucocorticoid receptor (GR) stimulation is co-regulated by tissue-specific metabolism via 11β-hydroxysteroid dehydrogenases that metabolize both glucocorticoids and adrenal-derived 11-oxygenated androgens, but with opposing effects on their bioactivity for their respective receptors. We used breast cancer cell lines with both AR and GR expression as a model to investigate the role of 11β-hydroxysteroid dehydrogenases for the co-regulation of AR and GR activity. Using liquid chromatography-tandem mass spectrometry, we show that breast cancer cells generate active 11-oxygenated androgens from abundant circulating adrenal precursors, while inactivating cortisol to cortisone. CRISPR/Cas editing showed that the oxidative activity of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is required for these metabolic conversions. Using RNA-Seq, we show that loss of HSD11B2 abolishes the induction of AR target genes in response to circulating 11-oxygenated androgen precursors while sustaining the induction of GR target genes in response to cortisol. Overexpression of the reductive 11β-hydroxysteroid dehydrogenase type 1 isoform, which catalyzes reactions opposing HSD11B2 activity, i.e. 11-oxygenated androgen inactivation and the reactivation of cortisol from cortisone, impairs the response of AR targets to 11-oxygenated androgens but promotes the response to glucocorticoids. We conclude that beyond the well-established role of 11β-hydroxysteroid dehydrogenases for the regulation of systemic and local GR activation, 11β-hydroxysteroid dehydrogenases additionally function as metabolic hubs that coordinate AR and GR activity by locally controlling the agonist levels for both receptors. Additionally, our results suggest that 11-oxygenated androgens are functionally distinct from classic androgens, such as testosterone, because they are specifically activated in the absence of glucocorticoid action due to their shared metabolic pathways.