title: The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling.
abstract: We identified the Rho GTPase Rnd1 as a candidate metastasis suppressor in basal-like and triple-negative breast cancer through bioinformatics analysis. Depletion of Rnd1 disrupted epithelial adhesion and polarity, induced epithelial-to-mesenchymal transition, and cooperated with deregulated expression of c-Myc or loss of p53 to cause neoplastic conversion. Mechanistic studies revealed that Rnd1 suppresses Ras signalling by activating the GAP domain of Plexin B1, which inhibits Rap1. Rap1 inhibition in turn led to derepression of p120 Ras-GAP, which was able to inhibit Ras. Inactivation of Rnd1 in mammary epithelial cells induced highly undifferentiated and invasive tumours in mice. Conversely, Rnd1 expression inhibited spontaneous and experimental lung colonization in mouse models of metastasis. Genomic studies indicated that gene deletion in combination with epigenetic silencing or, more rarely, point mutation inactivates RND1 in human breast cancer. These results reveal a previously unappreciated mechanism through which Rnd1 restrains activation of Ras-MAPK signalling and breast tumour initiation and progression.
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Okada
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: López-Lago
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Su
authors.affiliation: 1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Pediatrics, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Center of Experimental Medicine and Research, University of Torino, Torino 10126, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Abele
authors.affiliation: 1] Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Surgery, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hernandez
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohara
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.affiliation: Genomics Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Geoffrey Beene Translational Oncology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Bioinformatics Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Department of Medical Sciences, Center of Experimental Medicine and Research, University of Torino, Torino 10126, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Venkatraman E
authors.initials: VE
authors.lastname: Seshan
authors.affiliation: Structural Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Long
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Center of Experimental Medicine and Research, University of Torino, Torino 10126, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: 1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D020729:p120 GTPase Activating Protein / Q000096:biosynthesis; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors; D020703:ras GTPase-Activating Proteins / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C489427:MYC protein, human; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C491772:RND1 protein, human; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D020729:p120 GTPase Activating Protein; D020703:ras GTPase-Activating Proteins; D020827:rap1 GTP-Binding Proteins; D020741:rho GTP-Binding Proteins