title: Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy.
abstract: The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.
authors.affiliation: Department of Veterinary Physiology and Pharmacology Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466, USA Department of Food Science and Technology Keimyung University, Daegu 704701, Republic of Korea Department of Pharmaceutics College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Hedrick
authors.affiliation: Department of Veterinary Physiology and Pharmacology Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466, USA Department of Food Science and Technology Keimyung University, Daegu 704701, Republic of Korea Department of Pharmaceutics College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology and Pharmacology Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466, USA Department of Food Science and Technology Keimyung University, Daegu 704701, Republic of Korea Department of Pharmaceutics College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: Department of Veterinary Physiology and Pharmacology Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466, USA Department of Food Science and Technology Keimyung University, Daegu 704701, Republic of Korea Department of Pharmaceutics College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA ssafe@cvm.tamu.edu mandip.sacheva@gmail.com.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Veterinary Physiology and Pharmacology Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466, USA Department of Food Science and Technology Keimyung University, Daegu 704701, Republic of Korea Department of Pharmaceutics College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA ssafe@cvm.tamu.edu mandip.sacheva@gmail.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; D007211:Indoles; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species
keywords: NR4A1; antagonists; indole derivative