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 crosstalk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone (dex) exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR co-assembled on the BRK promoter in response to either hypoxia or dex, 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.

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

“…The study of GR's role in basal-like breast cancer has important clinical implications because potent synthetic glucocorticoids are often prescribed to breast cancer patients undergoing chemotherapy to prevent side-effects such as nausea, loss of appetite, and rare severe immune reactions. Our preliminary data supports a handful of other studies that report that induction of GR with glucocorticoids could promote tumor growth and therapy resistance (15,17,18,52). In our study specifically, it is clear that glucocorticoid induction of GR leads to increased cell proliferation in basal-like breast cancer cell lines and patient-derived organoids.…”

“…The role of many TFs have been studied in basal-like breast cancer, including oncogenic drivers such as MYC (6), and other TFs that regulate pathways associated with basal-like phenotypes such as EN1 (7), GLI1 (8), NF-kB (9), HIF1a (10), TWIST1 (11), FOXC1 (12,13), AP-1 (14), GR (15)(16)(17)(18), STAT3 (19,20), and MAFK (21). Many of these TFs regulate important pathways in basal-like breast cancer and these TFs often regulate each other's expression (22,23).…”

Cortisol and Breast Cancer: A review of clinical and molecular evidence

“…Anderson et al found there to be extensive cross-talk between the GR and the hypoxia-inducible factors (HIF) where the HIF created upregulation of Brk, a breast tumor kinase. The authors suggest that identifying ways to target and reduce Brk expression could be helpful in treating patients whose tumors are both PR and ER negative 43) .…”

Steroid Hormone Receptor Positive Breast Cancer Patient-Derived Xenografts

“…However, the divergent roles of these receptors in driving breast cancer growth complicates their use, and necessitates further study for patient selection [13, 14]. There is also recent interest in the role of GR in breast cancer, particularly the ER− subtypes [24–28]. PDX models that express each of these receptors in different combinations will be critical to evaluate new steroid receptor-targeted drugs and make selections for appropriate candidates for treatments.…”