title: Estrogen regulates JNK1 genomic localization to control gene expression and cell growth in breast cancer cells.
abstract: Steroid hormone and MAPK signaling pathways functionally intersect, but the molecular mechanisms of this cross talk are unclear. Here, we demonstrate a functional convergence of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways at the genomic level in breast cancer cells. We find that JNK1 binds to many promoters across the genome. Although most of the JNK1-binding sites are constitutive, a subset is estrogen regulated (either induced on inhibited). At the estrogen-induced sites, estrogen receptor (ER)α is required for the binding of JNK1 by promoting its recruitment to estrogen response elements or other classes of DNA elements through a tethering mechanism, which in some cases involves activating protein-1. At estrogen-regulated promoters, JNK1 functions as a transcriptional coregulator of ERα in a manner that is dependent on its kinase activity. The convergence of ERα and JNK1 at target gene promoters regulates estrogen-dependent gene expression outcomes, as well as downstream estrogen-dependent cell growth responses. Analysis of existing gene expression profiles from breast cancer biopsies suggests a role for functional interplay between ERα and JNK1 in the progression and clinical outcome of breast cancers.
authors.affiliation: Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8511, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Gary D
authors.initials: GD
authors.lastname: Isaacs
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fogarty
authors.forename: W Lee
authors.initials: WL
authors.lastname: Kraus
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004958:Estradiol; D048055:Mitogen-Activated Protein Kinase 8