Glucocorticoid Receptor Antagonism as a Novel Therapy for Triple-Negative Breast Cancer

Abstract

Purpose: Triple-negative breast cancer (TNBC) accounts for 10-20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC’s molecular heterogeneity. We have previously reported that, likely because of GR’s anti-apoptotic activity in ER-negative breast epithelial and cancer cells, high glucocorticoid receptor (GR) expression/activity in early-stage TNBC significantly correlates with chemotherapy-resistance and increased recurrence. We hypothesized that pre-treatment with mifepristone, a (GR)-antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBC by inhibiting GR’s anti-apoptotic signaling pathways and increasing the cytotoxic efficiency of chemotherapy. Experimental Design: TNBC cell apoptosis was examined in the context of physiological glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye, and Western analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel or mifepristone/paclitaxel. Results: We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression, while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo. Conclusions: These results suggest that mifepristone pre-treatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC.

Systematic Prioritization of Druggable Mutations in ∼5000 Genomes Across 16 Cancer Types Using a Structural Genomics-based Approach

“…GR agonists or antagonists had been approved for the treatment of allergic, inflammatory nasal conditions, and hypercortisolism, such as dexamethasone (agonist) and mifepristone (antagonist) (34). Skor et al showed that GR antagonisms provided a novel therapy for triple-negative breast cancer (62). GR agonist dexamethasone inhibits EGF-induced cell migration by modulating transcriptional activities in MCF10A mammary epithelial cells (63).…”

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

“…Notably Sgk1, as compared with its cognate kinase Akt, is highly regulated by steroids. Glucocorticoid receptor antagonism has been recently proposed as a promising therapy in triple negative breast cancer [27], and Sgk1 inhibition is thus expected to be at least as effective as glucocorticoid receptor antagonism.…”

The design and implementation of caloric restriction for oncology research (CaReFOR): Is starving cancer cells in the clinical realm feasible?

“…Patients chronically taking steroids are excluded since steroids are known to cause metabolic disturbances and may affect measured serum biomarkers. In addition, steroids themselves may have a therapeutic effect and could potentially confound results, as recent data has demonstrated a therapeutic effect in triple negative breast cancer [11]. Patients taking anti-retrovirals are also excluded since these medications are known to cause metabolic syndrome.…”