MON-262 11β-Hydroxysteroid Dehydrogenases are Metabolic Hubs Coordinating Androgen and Glucocorticoid Receptor Activation

Abstract Disclosure: L. Schiffer: None. K. Lomis: None. Y. Chung: None. N. Sharifi: None. Steroid receptors play broad and 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 the chromatin level. We hypothesized that local steroid metabolism is a major regulator of a switch between androgen receptor (AR) and glucocorticoid receptor (GR) stimulation via 11β-hydroxysteroid dehydrogenases that metabolize both glucocorticoids and adrenal-derived 11-oxygenated androgens, but with opposing effects on their activity for their respective receptors. Here, we used breast cancer with both AR and GR expression as a model to investigate the role of 11β-hydroxysteroid dehydrogenases for the regulation of AR and GR activity. Using liquid chromatography-tandem mass spectrometry, we show that breast cancer cell lines (T-47D and MCF-7) generate active 11-oxygenated androgens from the abundant circulating adrenal precursor 11β-hydroxyandrostenedione and inactivate cortisol to cortisone. Using CRISPR/Cas editing, we show that the oxidative activity of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is required for these metabolic conversions. HSD11B2 knock-out in T-47D and MCF-7 cells 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 (HSD11B1), 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 a metabolic hub that coordinates AR and GR activity by locally controlling their agonist levels. Additionally, our results suggest 11-oxygenated androgens are functionally distinct from classic androgens, such as testosterone, because due to their shared metabolic pathways with glucocorticoids they are activated in the absence of glucocorticoid action. Presentation: Monday, July 14, 2025