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Netrin-1 Expression Confers a Selective Advantage for Tumor Cell Survival in Metastatic Breast Cancer

Julien Fitamant, Céline Guenebeaud, Marie-May Coissieux, Catherine Guix, Isabelle Treilleux, Jean-Yves Scoazec, Thomas Bachelot, Agnès Bernet and Patrick Mehlen
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 12 (Mar. 25, 2008), pp. 4850-4855
Stable URL: http://www.jstor.org/stable/25461511
Page Count: 6
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Netrin-1 Expression Confers a Selective Advantage for Tumor Cell Survival in Metastatic Breast Cancer
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Abstract

Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.

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