title: Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer.
abstract: OBJECTIVE
  Triple-negative breast cancer (TNBC) accounts for 10% to 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 the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy.
  
  
  METHODS
  TNBC cell apoptosis was examined in the context of physiologic 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 blot 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 pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC.
authors.affiliation: Authors' Affiliations: Departments of Medicine, Health Studies, and Surgery, Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Maxwell N
authors.initials: MN
authors.lastname: Skor
authors.forename: Erin L
authors.initials: EL
authors.lastname: Wonder
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Anju
authors.initials: A
authors.lastname: Goyal
authors.forename: Ben A
authors.initials: BA
authors.lastname: Hall
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D015735:Mifepristone / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000893:Anti-Inflammatory Agents; D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; D006727:Hormone Antagonists; D017874:Immediate-Early Proteins; D015735:Mifepristone; D017239:Paclitaxel; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases; C517019:DUSP1 protein, human
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