title: Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.
abstract: Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Tarah M
authors.initials: TM
authors.lastname: Regan Anderson
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Shi Hong
authors.initials: SH
authors.lastname: Ma
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina.
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Taylor M
authors.initials: TM
authors.lastname: Helle
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Todd P
authors.initials: TP
authors.lastname: Knutson
authors.affiliation: Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee HSC, Memphis, Tennessee.
authors.forename: Raisa I
authors.initials: RI
authors.lastname: Krutilina
authors.affiliation: Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee HSC, Memphis, Tennessee.
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Seagroves
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. lange047@umn.edu.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Lange
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D003907:Dexamethasone; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C438485:PELP1 protein, human; C088375:PTK6 protein, human
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