title: Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression.
abstract: Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Hadas
authors: H
authors: Cohen-Dvashi
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Nir
authors: N
authors: Ben-Chetrit
authors: Cancer Research UK Cambridge Research Institute Li Ka Shing Centre, Cambridge, UK.
authors: Roslin
authors: R
authors: Russell
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Silvia
authors: S
authors: Carvalho
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Mattia
authors: M
authors: Lauriola
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Sophia
authors: S
authors: Nisani
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Maicol
authors: M
authors: Mancini
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Nishanth
authors: N
authors: Nataraj
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Merav
authors: M
authors: Kedmi
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Lee
authors: L
authors: Roth
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Wolfgang
authors: W
authors: Köstler
authors: Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors: Amit
authors: A
authors: Zeisel
authors: Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors: Assif
authors: A
authors: Yitzhaky
authors: Chemical Physics, Weizmann Institute of Science, Rehovot, Israel.
authors: Jacques
authors: J
authors: Zylberg
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Gabi
authors: G
authors: Tarcic
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Raya
authors: R
authors: Eilam
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Yoav
authors: Y
authors: Wigelman
authors: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Rainer
authors: R
authors: Will
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: Sara
authors: S
authors: Lavi
authors: Biological Services, Weizmann Institute of Science, Rehovot, Israel.
authors: Ziv
authors: Z
authors: Porat
authors: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Stefan
authors: S
authors: Wiemann
authors: IPATIMUP - Institute of Molecular Pathology and Immunology, Medical Faculty of the University of Porto, Porto, Portugal.
authors: Sara
authors: S
authors: Ricardo
authors: IPATIMUP - Institute of Molecular Pathology and Immunology, Medical Faculty of the University of Porto, Porto, Portugal.
authors: Fernando
authors: F
authors: Schmitt
authors: Cancer Research UK Cambridge Research Institute Li Ka Shing Centre, Cambridge, UK.
authors: Carlos
authors: C
authors: Caldas
authors: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel yosef.yarden@weizmann.ac.il.
authors: Yosef
authors: Y
authors: Yarden
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000150:complications* / Q000473:pathology*; D002465:Cell Movement; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C464453:NAV3 protein, human; D009419:Nerve Tissue Proteins
keywords: cancer; cell migration; cytoskeleton; growth factor; microtubules