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Cancer Res. 2016 Mar 15;76(6):1653-63. doi: 10.1158/0008-5472.CAN-15-2510. Epub 2016 Jan 29.

Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.

Author information

1
Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
2
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
3
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.
4
Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee HSC, Memphis, Tennessee.
5
Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. lange047@umn.edu.

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.

PMID:
26825173
PMCID:
PMC4794366
DOI:
10.1158/0008-5472.CAN-15-2510
[Indexed for MEDLINE]
Free PMC Article

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