title: Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly.
abstract: Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion of Akt2 increased median survival by 44%, neither organ overgrowth, nor hypoglycemia were rescued, indicating that both the growth and metabolic functions of constitutive PI3K activity can be Akt2 independent. This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level.
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kinross
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Montgomery
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Salvatore P
authors.initials: SP
authors.lastname: Mangiafico
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Hare
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Margarete
authors.initials: M
authors.lastname: Kleinschmidt
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Bywater
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Vrahnas
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Holger
authors.initials: H
authors.lastname: Henneicke
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Waring
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.affiliation: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia wayne.phillips@petermac.org.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D005947:Glucose; D007328:Insulin; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C546639:Pik3ca protein, mouse; C494922:Akt2 protein, mouse
keywords: PI3K; glucose metabolism; mouse model; overgrowth syndrome; p110α