Glucocorticoid receptors drive breast cancer cell migration and metabolic reprograming via pSer134-GR-induced expression of PDK4

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple negative breast cancers (TNBCs) account for 15-20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease, however the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (TGFß, HGF) activate p38 MAPK, which phosphorylates GR on Ser134. In the absence of ligand, p-Ser134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that GR Ser134 is required for TNBC metastatic colonization to the lung. To understand the mechanisms of p-Ser134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR (knock-in) models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and p-Ser134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9, CSF1, RUNX3) and metabolic adaptation (PDK4, PGK1, PFKFB4). TNBC cells harboring S134A GR displayed metabolic reprogramming that was phenocopied by PDK4 knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (i.e., host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease. Overall design: Examination of the effect of Dexamethasone in TNBC cell line MDA-MB-231 with mutation in the glucocorticoid receptor on Ser134.