Breast tumor kinase (Brk/PTK6) is induced by HIF, glucocorticoid receptor, and PELP1-mediated stress signaling in triple-negative breast cancer

Tarah M. Regan Anderson, Shi Hong Ma, Ganesh V. Raj, John A. Cidlowski, Taylor M. Helle, Todd P. Knutson, Raisa I. Krutilina, Tiffany N. Seagroves, Carol A. Lange

Research output: Contribution to journalArticle

15 Scopus citations

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-1a and HIF-2a. 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-2a, not HIF-1a, 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.

Original languageEnglish (US)
Pages (from-to)1653-1663
Number of pages11
JournalCancer Research
Volume76
Issue number6
DOIs
StatePublished - Mar 15 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Regan Anderson, T. M., Ma, S. H., Raj, G. V., Cidlowski, J. A., Helle, T. M., Knutson, T. P., Krutilina, R. I., Seagroves, T. N., & Lange, C. A. (2016). Breast tumor kinase (Brk/PTK6) is induced by HIF, glucocorticoid receptor, and PELP1-mediated stress signaling in triple-negative breast cancer. Cancer Research, 76(6), 1653-1663. https://doi.org/10.1158/0008-5472.CAN-15-2510