title: ATIP3, a novel prognostic marker of breast cancer patient survival, limits cancer cell migration and slows metastatic progression by regulating microtubule dynamics.
abstract: 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 8p22 MTUS1 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.
authors: Institut National de la Santé et de la Recherche Medicale (Inserm), U1016, Institut Cochin, France.
authors: Angie
authors: A
authors: Molina
authors: Lauriane
authors: L
authors: Velot
authors: Lydia
authors: L
authors: Ghouinem
authors: Mohamed
authors: M
authors: Abdelkarim
authors: Benjamin Pierre
authors: BP
authors: Bouchet
authors: Anny-Claude
authors: AC
authors: Luissint
authors: Imène
authors: I
authors: Bouhlel
authors: Marina
authors: M
authors: Morel
authors: Elène
authors: E
authors: Sapharikas
authors: Anne
authors: A
authors: Di Tommaso
authors: Stéphane
authors: S
authors: Honoré
authors: Diane
authors: D
authors: Braguer
authors: Nadège
authors: N
authors: Gruel
authors: Anne
authors: A
authors: Vincent-Salomon
authors: Olivier
authors: O
authors: Delattre
authors: Brigitte
authors: B
authors: Sigal-Zafrani
authors: Fabrice
authors: F
authors: André
authors: Benoit
authors: B
authors: Terris
authors: Anna
authors: A
authors: Akhmanova
authors: Mélanie
authors: M
authors: Di Benedetto
authors: Clara
authors: C
authors: Nahmias
authors: Sylvie
authors: S
authors: Rodrigues-Ferreira
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008870:Microtubules / Q000378:metabolism; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011379:Prognosis; D017434:Protein Structure, Tertiary; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C474762:MTUS1 protein, human; D025521:Tumor Suppressor Proteins