Authors
Posani, S. H., Diep, C. H., Krutilina, R. I., Smith, H., Seagroves, T. N., Blenis, J., Lange, C. A.
Abstract
In triple-negative breast cancer (TNBC), p38 MAPK phosphorylates the glucocorticoid receptor (GR) at N-terminal Ser134 in response to cytokines, such as TGF{beta}1. Phospho-Ser134-GR (pSer134-GR) regulates genes that promote migratory/invasive behavior and altered metabolism. In addition to acting as ligands for GR, glucocorticoids also activate closely-related mineralocorticoid receptors (MR). Elevated MR activity via its physiological ligand aldosterone (aldo), mediates hypertension, inflammation and fibrosis. While GR/p-GR has been implicated in TNBC progression to metastasis, the contribution of MR remains unknown. The METABRIC dataset demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancers. Further, high MR expression predicted worse overall survival in the KM-plotter database. We observed pSer134-GR- and p38-dependent association of cytoplasmic MR/p-GR complexes upon treatment of TNBC cells with TGF{beta}1, while nuclear MR-GR complexes predominated in response to dexamethasone (dex) and/or aldo. Cytoplasmic MR/p-GR complexes entered the nucleus within 4 hours. MR knockdown or inhibition with MR-selective antagonists (spironolactone, finerenone) significantly reduced aldo or TGF{beta}1-induced migratory and stemness properties. MR knockdown models exhibited reduced migration, attenuated stem cell expansion, and impaired metastasis to lungs following tail-vein injection, thereby phenocopying cells harboring phospho-mutant S134A-GR. MR activation by aldo or TGF{beta}1 transcriptionally upregulated both canonical MR-target genes (SGK1, ENaC1) and non-canonical target genes related to fibrosis (COL1A1, ICAM1 and CTGF). MR expression was essential for functionally intact p38 MAPK/p-Ser134-GR signaling downstream of TGF{beta}1 receptor activation. Our studies define a novel role of MR/p-GR complexes in regulation of TNBC cell migration, stemness potential, and metastasis. Pharmacological inhibition of MR with FDA-approved MR antagonists (MRAs) offers an exciting opportunity for improved clinical management of TNBC patients.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Nov 2025.
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