title: DDB2: a novel regulator of NF-κB and breast tumor invasion.
abstract: The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.
authors.affiliation: Centre de Recherche en Automatique de Nancy (CRAN), UMR 7039 Centre National de la Recherche Scientifique (CNRS), Université de Lorraine, Faculté des Sciences et Technologies, Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Ennen
authors.forename: Rémi
authors.initials: R
authors.lastname: Klotz
authors.forename: Nadège
authors.initials: N
authors.lastname: Touche
authors.forename: Sophie
authors.initials: S
authors.lastname: Pinel
authors.forename: Claire
authors.initials: C
authors.lastname: Barbieux
authors.forename: Vanessa
authors.initials: V
authors.lastname: Besancenot
authors.forename: Emilie
authors.initials: E
authors.lastname: Brunner
authors.forename: Denise
authors.initials: D
authors.lastname: Thiebaut
authors.forename: Alain C
authors.initials: AC
authors.lastname: Jung
authors.forename: Sonia
authors.initials: S
authors.lastname: Ledrappier
authors.forename: Lionel
authors.initials: L
authors.lastname: Domenjoud
authors.forename: Joseph
authors.initials: J
authors.lastname: Abecassis
authors.forename: François
authors.initials: F
authors.lastname: Plénat
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Grandemange
authors.forename: Philippe
authors.initials: P
authors.lastname: Becuwe
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9