title: Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer.
abstract: Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5'-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Ben-Chetrit
authors.affiliation: Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Chetrit
authors.affiliation: Department of Oncology and Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Körner
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maicol
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Kaplan Medical Center, Rehovot 76100, Israel.
authors.forename: Ali
authors.initials: A
authors.lastname: Abdul-Hai
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Cohen-Dvashi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Koestler
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
authors.forename: Kirti
authors.initials: K
authors.lastname: Shukla
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Moshit
authors.initials: M
authors.lastname: Lindzen
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Kedmi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.affiliation: INCPM, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Barr
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dalia
authors.initials: D
authors.lastname: Seger
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Ferraro
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Fresia
authors.initials: F
authors.lastname: Pareja
authors.affiliation: Faculty of Medicine, Bar-Ilan University, Safed 13115, Israel.
authors.forename: Hava
authors.initials: H
authors.lastname: Gil-Henn
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.affiliation: IPATIMUP, University of Porto, Porto 4200-465, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Milanezi
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Ben-Hamo
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Sol
authors.initials: S
authors.lastname: Efroni
authors.affiliation: IPATIMUP, University of Porto, Porto 4200-465, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Department of Oncology and Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. yosef.yarden@weizmann.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055808:Drug Discovery; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D008855:Microscopy, Electron, Scanning; D009362:Neoplasm Metastasis / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000069261:Podosomes / Q000235:genetics / Q000502:physiology; D011554:Pseudopodia / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D018709:Statistics, Nonparametric; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases; D034741:RNA, Small Interfering; D000099182:Phosphoinositide 5-Phosphatases