{"doi":"10.1210/endocr/bqad083","title":"Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4","abstract":"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% to 20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but they 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 (transforming growth factor β [TGF-β], hepatocyte growth factor [HGF]) activate p38 mitogen-activated protein kinase (MAPK), which phosphorylates GR on Ser134. In the absence of ligand, pSer134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that pSer134-GR is required for TNBC metastatic colonization to the lungs of female mice. To understand the mechanisms of pSer134-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 pSer134-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 pyruvate dehydrogenase kinase 4 (PDK4) knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (ie, host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease.","journal":"Endocrinology","year":2023,"id":323976,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299733,"name":"Carlos Perez Kerkvliet","orcid":"0000-0003-2530-840X","position":1,"is_corresponding":false},{"id":355379,"name":"Thu H. Truong","orcid":"0000-0003-2394-551X","position":2,"is_corresponding":false},{"id":583905,"name":"Kyla M. Hagen","orcid":null,"position":3,"is_corresponding":false},{"id":360690,"name":"Raisa I. Krutilina","orcid":"0000-0002-2118-4019","position":4,"is_corresponding":false},{"id":360692,"name":"Deanna N. Parke","orcid":"0000-0001-5125-683X","position":5,"is_corresponding":false},{"id":299736,"name":"Robert H. Oakley","orcid":"0000-0001-7317-2223","position":6,"is_corresponding":false},{"id":233005,"name":"Christopher Liddle","orcid":"0000-0003-3936-6790","position":7,"is_corresponding":false},{"id":267572,"name":"John A. Cidlowski","orcid":"0000-0003-1420-0516","position":8,"is_corresponding":false},{"id":360693,"name":"Tiffany N. Seagroves","orcid":"0000-0002-6937-943X","position":9,"is_corresponding":false},{"id":299737,"name":"Carol A. Lange","orcid":"0000-0003-2751-3976","position":10,"is_corresponding":false},{"id":299734,"name":"Amy R. Dwyer","orcid":"0000-0002-4422-1433","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:08:06.496579Z","pmid":"37224504","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}