title: Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference.
abstract: In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so-called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro-apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation-dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin-1 dependence receptor pro-apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin-1-low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti-netrin-1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin-1 neutralizing agents may be a valuable strategy for combating cancer.
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Mélodie
authors.initials: M
authors.lastname: Grandin
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Mathot
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Devailly
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bidet
authors.affiliation: Epigenetics Group, IARC, Lyon, France.
authors.forename: Akram
authors.initials: A
authors.lastname: Ghantous
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Clementine
authors.initials: C
authors.lastname: Favrot
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gibert
authors.affiliation: Endocrine Differentiation Laboratory, CRCL Université de Lyon Hospices Civils de Lyon Hôpital Edouard Herriot Anatomie Pathologique, Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.affiliation: Targeting of the tumor and its immune environment Laboratory CRCL INSERM U1052 CNRS UMR5286 UCBL CLB, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Puisieux
authors.affiliation: Epigenetics Group, IARC, Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Delcros
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Bernet
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France patrick.mehlen@lyon.unicancer.fr robert.dante@lyon.unicancer.fr.
authors.forename: Patrick
authors.identifier: 0000-0001-8070-7695
authors.initials: P
authors.lastname: Mehlen
authors.affiliation: Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286 Université de Lyon Centre Léon Bérard, Lyon, France patrick.mehlen@lyon.unicancer.fr robert.dante@lyon.unicancer.fr.
authors.forename: Robert
authors.initials: R
authors.lastname: Dante
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000096:biosynthesis; D015536:Down-Regulation; D006801:Humans; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D000075388:Netrin-1; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
keywords: DNA methylation; apoptosis; breast cancer; decitabine; dependence receptor