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 ( 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. image A new potential suppressor of metastasis, Navigator‐3, acts by modulating migration patterns and conferring a lower probability to locate tissue escape routes. Navigator‐3 ( NAV 3), a nerve‐navigating gene of worms and a gene frequently mutated or deleted in human tumors, was identified herein as a potential suppressor of metastasis, which associates with good prognosis of breast cancer patients. The NAV 3 protein localizes to the growing end of microtubules, enhances their growth and augments the ability of cells to adhere to a migration course, while also slowing down migration rates. Animal studies indicate that these cellular actions of NAV 3 overall reduce the capacity of tumor cells to form metastases, and mathematical modeling attributes this to lower probability to locate rare or transient targets, such as escape routes within tissues. NAV 3 cancer mutations affect different protein domains; analysis of two point mutants uncovered a destabilization effect, suggesting loss of function in cancer.