title: The critical role of the ZNF217 oncogene in promoting breast cancer metastasis to the bone.
abstract: Bone metastasis affects >70% of patients with advanced breast cancer. However, the molecular mechanisms underlying this process remain unclear. On the basis of analysis of clinical datasets, and in vitro and in vivo experiments, we report that the ZNF217 oncogene is a crucial mediator and indicator of bone metastasis. Patients with high ZNF217 mRNA expression levels in primary breast tumours had a higher risk of developing bone metastases. MDA-MB-231 breast cancer cells stably transfected with ZNF217 (MDA-MB-231-ZNF217) showed the dysregulated expression of a set of genes with bone-homing and metastasis characteristics, which overlapped with two previously described 'osteolytic bone metastasis' gene signatures, while also highlighting the bone morphogenetic protein (BMP) pathway. The latter was activated in MDA-MB-231-ZNF217 cells, and its silencing by inhibitors (Noggin and LDN-193189) was sufficient to rescue ZNF217-dependent cell migration, invasion or chemotaxis towards the bone environment. Finally, by using non-invasive multimodal in vivo imaging, we found that ZNF217 increases the metastatic growth rate in the bone and accelerates the development of severe osteolytic lesions. Altogether, the findings of this study highlight ZNF217 as an indicator of the emergence of breast cancer bone metastasis; future therapies targeting ZNF217 and/or the BMP signalling pathway may be beneficial by preventing the development of bone metastases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bellanger
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.|Unité Cancer et Environnement, Centre Léon Bérard, Lyon, France.
authors.forename: Caterina F
authors.initials: CF
authors.lastname: Donini
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vendrell
authors.affiliation: INSERM U1209, Institut Albert Bonniot, Grenoble, France.|Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lavaud
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.|INSERM, Unit 1033 (Faculté de Médecine Lyon Est), Lyon, France.
authors.forename: Irma
authors.initials: I
authors.lastname: Machuca-Gayet
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Maëva
authors.initials: M
authors.lastname: Ruel
authors.affiliation: INSERM U1209, Institut Albert Bonniot, Grenoble, France.|Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vollaire
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Grisard
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Unit of Pharmacogenetics, Department of Genetics, Institut Curie, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.|INSERM, Unit 1033 (Faculté de Médecine Lyon Est), Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peyruchaud
authors.affiliation: INSERM U1209, Institut Albert Bonniot, Grenoble, France.|Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.affiliation: Département de Biopathologie, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Maguer-Satta
authors.affiliation: INSERM U1209, Institut Albert Bonniot, Grenoble, France.|Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.affiliation: Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Pascale A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D016723:Bone Remodeling / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D019485:Bone Morphogenetic Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015534:Trans-Activators; C113698:ZNF217 protein, human
keywords: BMP pathway; ZNF217; bone metastasis; breast cancer; oncogene