Tumor and Stem Cell Biology ATIP 3 , a Novel Prognostic Marker of Breast Cancer Patient Survival , Limits Cancer Cell Migration and Slows Metastatic Progression by Regulating Microtubule Dynamics

Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression. Cancer Res; 73(9); 2905–15. 2013 AACR. Introduction The occurrence of distant metastasis is a dreadful complication of breast cancer and a leading cause of death by malignancy in women worldwide. Metastasis is a multistep process that involves cancer cell migration and invasion across the extracellular matrix to reach the blood flow, followed by extravasation and colonization of secondary organs (1). Among millions of invasive cancer cells that reach the blood circulation, only few will establish at distant sites and grow as metastases (2–5). Breast cancer metastases can remain latent for several years following primary tumor removal, and the identification ofmolecularmarkers thatmay predict the risk of metastasis occurrence, and/or progression is of invaluable help for the follow-up of the patients and choice of therapeutic options (5, 6). Over the past decade, extensive studies have led to the classification of breast tumors into distinct molecular subtypes, allowing subsequent development of efficient targeted treatments for a majority of primary tumors (7–9). However, available therapies have limited effect on cancer metastasis and new genetic determinants contributing to essential steps of the metastatic process need to be characterized. Microtubule-targeting drugs such as taxanes are used for standard first-line treatment of breast cancer metastasis, and new microtubule-targeting agents, such as epothilones and eribulin, are under clinical evaluation (10). Microtubules are polarized and highly dynamic structures that rapidly switch between periods of polymerization (growth) and depolymerization (shrinkage) at the plus ends, a process termed dynamic Authors' Affiliations: Institut National de la Sant e et de la Recherche Medicale (Inserm), U1016, Institut Cochin; CNRS, UMR8104; Universit e Paris Descartes, Sorbonne Paris Cit e; CNRS7033, UMRS940, IGM; Institut National de la Sant e et de la Recherche Medicale (Inserm), U830, Translational ResearchDepartment, InstitutCurie; PathologyDepartment, Hopital Cochin, Paris; Universit e Paris 13, Bobigny; Aix-Marseille University, CRO2, Institut National de la Sant e et de la Recherche Medicale (Inserm) UMR911, Marseille; Department of Medicine, Institut Gustave Roussy, Institut National de la Sant e et de la Recherche Medicale (Inserm), U981, Villejuif, France, and Cell Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). C. Nahmias and S. Rodrigues-Ferreira contributed equally to this work. Corresponding Author:Clara Nahmias, Institut Cochin, Dept EMC, 22 rue M echain 75014 Paris, France. Phone: 33-1405-16410; Fax: 33-140516430; E-mail: clara.nahmias@inserm.fr doi: 10.1158/0008-5472.CAN-12-3565 2013 American Association for Cancer Research. Cancer Research www.aacrjournals. org 2905 on August 20, 2017. © 2013 American Association for Cancer Research. cancerres.aacrjournals. org Downloaded from Published OnlineFirst February 8, 2013; DOI: 10.1158/0008-5472.CAN-12-3565