title: NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration.
abstract: Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3'-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Hedrick
authors.affiliation: Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea.
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; D019012:Integrin beta1; D039661:Integrin beta3; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D010648:Phenylacetates; D016212:Transforming Growth Factor beta; C000610380:p-carboxymethylphenyl 1,1-bis(3'-indolyl)-1-(p-carboxymethylphenyl)methane