title: The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers.
abstract: Disease progression and recurrence are major barriers to survival for breast cancer patients. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly overexpressed breast cancer oncogenes, Ron (Recepteur d'Origine Nantaise) and DEK, cooperate to promote advanced disease through multipronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron overexpression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis and fewer cells expressing mammary cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek overexpression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK overexpression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: L M
authors: LM
authors: Privette Vinnedge
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: N M
authors: NM
authors: Benight
authors: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: P K
authors: PK
authors: Wagh
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: N A
authors: NA
authors: Pease
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: M A
authors: MA
authors: Nashu
authors: 1] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA [2] IMIBIC/UCO/University Hospital Reina Sofia, Cordoba, Spain.
authors: J
authors: J
authors: Serrano-Lopez
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: A K
authors: AK
authors: Adams
authors: 1] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA [2] Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: J A
authors: JA
authors: Cancelas
authors: 1] Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA [2] Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH, USA.
authors: S E
authors: SE
authors: Waltz
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: S I
authors: SI
authors: Wells
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental; D015513:Oncogene Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases