title: Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells.
abstract: REV-ERBα and REV-ERBβ are nuclear receptors that are ligand-dependent transcriptional repressors. Heme is the natural ligand for these receptors, but several synthetic agonists and antagonists have been designed recently. The gene that encodes REV-ERBα, NR1D1, is closely associated with ERBB2, the gene that encodes the HER2 oncogene, which is amplified in HER2(+) breast cancers. We examined the effect of a synthetic REV-ERB agonist, SR9011, on a range of estrogen receptor positive (ER(+)), ER(-), HER2(+), HER2(-) and triple negative breast cancer cell lines. We found that SR9011 suppressed proliferation of the breast cancer cell lines regardless of their ER or HER2 status. SR9011 had no effect on MCF10A cell proliferation. SR9011 appears to pause the cell cycle of the breast cancer cells prior to M phase. Cyclin A (CCNA2) was identified as a direct target gene of REV-ERB suggesting that suppression of expression of this cyclin by SR9011 may mediate the cell cycle arrest. These data indicate that synthetic REV-ERB ligands may hold utility in treatment of diseases associated with uncontrolled cellular proliferation such as cancer.
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, United States.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Scripps Research Institute, Jupiter, FL 33458, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Kojetin
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, United States. Electronic address: burristp@slu.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists*; D011759:Pyrrolidines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011759:Pyrrolidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013876:Thiophenes; C064353:NR1D1 protein, human; C572450:SR9011; C508053:ERBB2 protein, human
keywords: Cell cycle; Circadian rhythm; Heme; Nuclear receptor; Steroid receptor