In normal physiology, glucocorticoid receptor (GR) activation regulates cell type-dependent genes whose products influence metabolism, inflammation, cell cycle and apoptosis/cell survival pathways. Synthetic GR agonists, or glucocorticoids (GCs), are often used to treat hematologic malignancies because of GRs ability to induce proapoptotic gene expression, inhibit nuclear factorκB, and induce cell cycle arrest. In contrast, recent examination of GR expression and activity in human cancer models and clinical specimens has suggested that GR activity has remarkably diverse roles in breast and prostate cancer subtypes. In estrogen receptor (ER)+ breast cancer, GR appears to modulate ER-regulated transcriptional activity through ER/GR receptor crosstalk resulting in antagonism of ER-associated proliferation. However, in ER-negative breast cancer (including TNBC), high tumor GR expression is associated with poor prognosis, anti-apoptotic signaling, and chemotherapy resistance. In addition, high GR activity in castrate-resistant prostate cancer (CRPC) contributes to therapy-resistance to androgen receptor (AR) antagonism. Recently described selective GR modulators will be described that have been used to dissect divergent GR mechanisms present in breast cancer subtypes and prostate cancer evolution.
27 Feb - 02 Mar 2018
Nuclear Receptors Conference