title: Intestinal-specific activatable Myb initiates colon tumorigenesis in mice.
abstract: Transcription factor Myb is overexpressed in most colorectal cancers (CRC). Patients with CRC expressing the highest Myb are more likely to relapse. We previously showed that mono-allelic loss of Myb in an Adenomatous polyposis coli (APC)-driven CRC mouse model (Apc(Min/+)) significantly improves survival. Here we directly investigated the association of Myb with poor prognosis and how Myb co-operates with tumor suppressor genes (TSGs) (Apc) and cell cycle regulator, p27. Here we generated the first intestinal-specific, inducible transgenic model; a MybER transgene encoding a tamoxifen-inducible fusion protein between Myb and the estrogen receptor-α ligand-binding domain driven by the intestinal-specific promoter, Gpa33. This was to mimic human CRC with constitutive Myb activity in a highly tractable mouse model. We confirmed that the transgene was faithfully expressed and inducible in intestinal stem cells (ISCs) before embarking on carcinogenesis studies. Activation of the MybER did not change colon homeostasis unless one p27 allele was lost. We then established that MybER activation during CRC initiation using a pro-carcinogen treatment, azoxymethane (AOM), augmented most measured aspects of ISC gene expression and function and accelerated tumorigenesis in mice. CRC-associated symptoms of patients including intestinal bleeding and anaemia were faithfully mimicked in AOM-treated MybER transgenic mice and implicated hypoxia and vessel leakage identifying an additional pathogenic role for Myb. Collectively, the results suggest that Myb expands the ISC pool within which CRC is initiated while co-operating with TSG loss. Myb further exacerbates CRC pathology partly explaining why high MYB is a predictor of worse patient outcome.
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: J
authors: J
authors: Malaterre
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: L
authors: L
authors: Pereira
authors: Walter and Elisa Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors: T
authors: T
authors: Putoczki
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: R
authors: R
authors: Millen
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: S
authors: S
authors: Paquet-Fifield
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: M
authors: M
authors: Germann
authors: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: J
authors: J
authors: Liu
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Walter and Elisa Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors: D
authors: D
authors: Cheasley
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: S
authors: S
authors: Sampurno
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: S A
authors: SA
authors: Stacker
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: M G
authors: MG
authors: Achen
authors: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: R L
authors: RL
authors: Ward
authors: Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Medicine, Sydney, New South Wales, Australia.
authors: P
authors: P
authors: Waring
authors: Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Medicine, Sydney, New South Wales, Australia.
authors: T
authors: T
authors: Mantamadiotis
authors: Walter and Elisa Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors: M
authors: M
authors: Ernst
authors: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Medicine, Sydney, New South Wales, Australia.
authors: R G
authors: RG
authors: Ramsay
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D013234:Stem Cells / Q000473:pathology; D000072258:Tumor Hypoxia; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse