title: Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data.
abstract: BACKGROUND
  WNT signaling is a complex process comprising multiple pathways: the canonical β-catenin-dependent pathway and several alternative non-canonical pathways that act in a β-catenin-independent manner. Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e.g. high-throughput data.
  
  
  RESULTS
  In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases. The data were assembled to construct computationally suitable models of different WNT signaling cascades in the form of directed signaling graphs. This resulted in four networks representing canonical WNT signaling, non-canonical WNT signaling, the inhibition of canonical WNT signaling and the regulation of WNT signaling pathways, respectively. Furthermore, these networks were integrated with microarray and RNA sequencing data to gain deeper insight into the underlying biology of gene expression differences between MCF-7 and MDA-MB-231 breast cancer cell lines, representing weakly and highly invasive breast carcinomas, respectively. Differential genes up-regulated in the MDA-MB-231 compared to the MCF-7 cell line were found to display enrichment in the gene set originating from the non-canonical network. Moreover, we identified and validated differentially regulated modules representing canonical and non-canonical WNT pathway components specific for the aggressive basal-like breast cancer subtype.
  
  
  CONCLUSIONS
  In conclusion, we demonstrated that these newly constructed WNT networks reliably reflect distinct WNT signaling processes. Using transcriptomic data, we shaped these networks into comprehensive modules of the genes implicated in the aggressive basal-like breast cancer subtype and demonstrated that non-canonical WNT signaling is important in this context. The topology of these networks can be further refined in the future by integration with complementary data such as protein-protein interactions, in order to gain greater insight into signaling processes.
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bayerlová
authors.affiliation: Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kramer
authors.affiliation: Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.|Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Beißbarth
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.|Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins