title: Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.
abstract: Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and.
authors.forename: Joan
authors.initials: J
authors.lastname: Font-Burgada
authors.affiliation: Departments of Pharmacology.
authors.forename: Trenis
authors.initials: T
authors.lastname: Palmer
authors.affiliation: Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hamil
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648;
authors.forename: Subhra K
authors.initials: SK
authors.lastname: Biswas
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648; Department of Biological Sciences, National University of Singapore, Singapore 117543;
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Borcherding
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Pathology, and.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.affiliation: Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
authors.forename: Nikki K
authors.initials: NK
authors.lastname: Lytle
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Li-Wha
authors.initials: LW
authors.lastname: Wu
authors.affiliation: Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Fox
authors.affiliation: Departments of Pharmacology.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dowdy
authors.affiliation: Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
authors.forename: Tannishtha
authors.initials: T
authors.lastname: Reya
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and karinoffice@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D044763:Ubiquitin-Conjugating Enzymes; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C471607:UBE2N protein, human
keywords: pre-clinical studies; ubiquitination-mediated signaling