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Navigator‐3, a modulator of cell migration, may act as a suppressor of breast cancer progression

2015; Springer Nature; Volume: 7; Issue: 3 Linguagem: Inglês

10.15252/emmm.201404134

1757-4684

Hadas Cohen‐Dvashi, Nir Ben‐Chetrit, Roslin Russell, Sílvia Carvalho, Mattia Lauriola, Sophia Nisani, Maicol Mancini, Nishanth Belugali Nataraj, Merav Kedmi, L. E. Roth, Wolfgang J. Köstler, Amit Zeisel, Assif Yitzhaky, Jacques Zylberg, Gabi Tarcic, Raya Eilam, Yoav Wigelman, Rainer Will, Sara Lavi, Ziv Porat, Stefan Wiemann, Sara Ricardo, Fernando Schmitt, Carlos Caldas, Yosef Yarden,

Hippo pathway signaling and YAP/TAZ

Abstract Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator‐3 ( NAV 3 ), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV 3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV 3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV 3‐depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV 3 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 NAV 3 with shorter survival. We propose that NAV 3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.