SUN-287 - Glucocorticoid Receptors Integrate Tgfβ1 Signaling and Autocrine Cortisol Biosynthesis to Promote Triple-Negative Breast Cancer Progression

Triple-negative breast cancer (TNBC) accounts for 10-15% of breast cancer cases and lacks targeted therapies due to the absence of estrogen and progesterone receptors and HER2 amplification. In TNBC, the glucocorticoid receptor (GR) is the most highly expressed steroid receptor and high GR expression predicts poor clinical outcomes. GR is a known mediator of progression and metastasis in TNBC, but the mechanism behind these observations is incompletely understood. While canonical activation of GR is ligand-dependent, our lab has previously described a ligand-independent mechanism of GR activation in response to TGFß1, establishing GR as a downstream-effector of TGFß1-driven advanced cancer phenotypes. TGFß1 induces p38-MAPK-dependent phosphorylation of GR at serine 134 (Ser134); this singular event was required for TNBC cell migration, stemness phenotypes, and expression of gene sets associated with extremely poor TNBC outcome. TGFß1 is a driver of breast cancer migration and metastasis, but also has anti-proliferative effects on premalignant epithelial cells complicating the efficacy of targeting TGFß1 directly. TGFß1 induces expression of epithelial-mesenchymal transition (EMT)-related genes and our preliminary data demonstrates that TGFß1 also induces altered glucocorticoid biosynthesis, increasing cortisol production. Specifically, TGFß1 treatment increases expression of 11ß-HSD1, encoded by HSD11B1, an enzyme that enables glucocorticoid recycling by reducing inactive cortisone to the active hormone cortisol, a cognate ligand of GR. Upregulation of HSD11B1 by TGFß1 increased production of cortisol by MDA-MB-231 cells in vitro. Antagonism of GR with relacorilant blocked the upregulation of HSD11B1 and markers of EMT, suggesting that GR is a necessary effector of TGFß1-induced EMT and upregulation of HSD11B1. Our analyses of public clinical data further revealed that high HSD11B1 expression correlates with significantly decreased overall survival specifically in TNBC patients. Together, our preliminary data suggest that a feed-forward loop between ligand-independent activation of GR and increased cortisol production capable of sustaining ligand-dependent GR action could contribute to the poor outcomes associated with GR and HSD11B1 expression in TNBC. The long-term goal of this work is to elucidate the role of autocrine cortisol production and evaluate the therapeutic potential of targeting 11ß-HSD1 on TGFß1 action and GR-mediated progression of TNBC.

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