Mineralocorticoid and glucocorticoid receptor cooperation drives advanced phenotypes in triple-negative breast cancer

Oncogenic cell signaling, including the activation of cellular stress or cytokine-induced pathways, is a hallmark of cancer. In triple-negative breast cancer (TNBC), p38 MAPK phosphorylates glucocorticoid receptors (GR) at Ser134 in response to cytokines such as TGFβ1. This activated Phospho-Ser134-GR (pSer134-GR) regulates genes promoting cancer cell migration, invasion, and altered metabolism. Glucocorticoids also activate the functionally and structurally-related mineralocorticoid receptors (MR) whose ligand, aldosterone, mediates hypertension, inflammation and fibrosis. We and others have previously shown the role of GR in the advanced phenotypes exhibited by TNBC, but the potential importance of GR-MR crosstalk and the specific contribution of MR remains unknown. Interestingly, our new analyses of MR expression in TNBC tumors revealed elevated MR transcript levels relative to luminal breast cancer subtypes, which are predictive of worse overall survival. Cytoplasmic MR-GR complexes that are formed upon treatment of TNBC cells with TGFβ1 required both p38 MAPK signaling and pSer134-GR. In contrast, nuclear MR-GR complexes predominated in response to dexamethasone and/or aldosterone. MR antagonists (spironolactone, finerenone) significantly reduced aldosterone- or TGFβ1-induced migratory and stemness properties and blocked MR-pGR and MR-GR interactions; MR knockdown similarly attenuated these advanced cancer phenotypes. MR expression was essential for both a functional p38 MAPK module and pSer134-GR downstream of TGFβ1 receptor activation. Crucially, MR-deficient models exhibited reduced lung metastasis following mouse tail-vein injection, phenocopying cells harboring phospho-mutant S134A-GR. As with p-Ser134-GR, we define a novel role for MR-GR cooperation downstream of TGFβ1 for regulation of TNBC cell migration, stemness, and in vivo lung colonization.