title: DRO1 inactivation drives colorectal carcinogenesis in ApcMin/+ mice.
abstract: Colorectal cancer develops from adenomatous precursor lesions by a multistep process that involves several independent mutational events in oncogenes and tumor suppressor genes. Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is an early event and a prerequisite for the development of human colorectal adenoma. Previous in vitro studies identified DRO1 (CCDC80) to be a putative tumor suppressor gene that is negatively regulated in colorectal cancers and downregulated upon neoplastic transformation of epithelial cells. To investigate the in vivo role of DRO1 in colorectal carcinogenesis, a constitutive DRO1 knockout mouse model was generated. Disruption of DRO1 did not result in spontaneous intestinal tumor formation, consistent with the notion that DRO1 might have a role in suppressing the development of colon tumors in Apc(Min) (/+) mice, a widely used model for studying the role of APC in intestinal tumorigenesis that is hampered by the fact that mice predominantly develop adenomas in the small intestine and not in the colon. Here, deletion of DRO1 in Apc(Min) (/+) mice results in earlier death, a dramatically increased colonic tumor burden, and frequent development of colorectal carcinoma. Furthermore, enhanced phosphorylation of ERK1/2 is observed in colon epithelium and tumors from DRO1 knockout mice. Thus, this study reveals that inactivation of DRO1 is required for colorectal carcinogenesis in the Apc(Min) (/+) mouse and establishes a new mouse model for the study of colorectal cancer.
  
  
  CONCLUSIONS
  This report characterizes a new mouse model for the study of colorectal cancer and establishes DRO1 (CCDC80) as a tumor suppressor via a mechanism involving ERK phosphorylation.
authors: Department of Internal Medicine II, University of Munich, Munich, Germany. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Munich, Germany.
authors: Jessica I
authors: JI
authors: Grill
authors: Institute of Pathology, University of Munich, Munich, Germany.
authors: Jens
authors: J
authors: Neumann
authors: Department of Internal Medicine II, University of Munich, Munich, Germany.
authors: Andreas
authors: A
authors: Herbst
authors: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Munich, Germany.
authors: Felix
authors: F
authors: Hiltwein
authors: Department of Internal Medicine II, University of Munich, Munich, Germany.
authors: Andrea
authors: A
authors: Ofner
authors: Department of Internal Medicine II, University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center, Heidelberg, Germany.
authors: Maximilian K
authors: MK
authors: Marschall
authors: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Munich, Germany.
authors: Eckhard
authors: E
authors: Wolf
authors: Institute of Pathology, University of Munich, Munich, Germany.
authors: Thomas
authors: T
authors: Kirchner
authors: Department of Internal Medicine II, University of Munich, Munich, Germany.
authors: Burkhard
authors: B
authors: Göke
authors: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Munich, Germany.
authors: Marlon R
authors: MR
authors: Schneider
authors: Department of Internal Medicine II, University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center, Heidelberg, Germany. fkolligs@med.uni-muenchen.de.
authors: Frank T
authors: FT
authors: Kolligs
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016326:Extracellular Matrix Proteins; D005260:Female; D017353:Gene Deletion; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C448780:Ccdc80 protein, mouse; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins