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none 27 si 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. Hadas Cohen-Dvashi1, Nir Ben-Chetrit1, Roslin Russell2, Silvia Carvalho1, Mattia Lauriola1,‡, Sophia Nisani1, Maicol Mancini1, Nishanth Nataraj1, Merav Kedmi1, Lee Roth1, Wolfgang Köstler1,†, Amit Zeisel3, Assif Yitzhaky3, Jacques Zylberg4, Gabi Tarcic1, Raya Eilam1, Yoav Wigelman1, Rainer Will5, Sara Lavi1, Ziv Porat6, Stefan Wiemann5, Sara Ricardo7, Fernando Schmitt7, Carlos Caldas2 & Yosef Yarden1,* Hadas Cohen-Dvashi1, Nir Ben-Chetrit1, Roslin Russell2, Silvia Carvalho1, Mattia Lauriola1,‡, Sophia Nisani1, Maicol Mancini1, Nishanth Nataraj1, Merav Kedmi1, Lee Roth1, Wolfgang Köstler1,†, Amit Zeisel3, Assif Yitzhaky3, Jacques Zylberg4, Gabi Tarcic1, Raya Eilam1, Yoav Wigelman1, Rainer Will5, Sara Lavi1, Ziv Porat6, Stefan Wiemann5, Sara Ricardo7, Fernando Schmitt7, Carlos Caldas2 & Yosef Yarden1,*