title: The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis.
abstract: BACKGROUND
  The establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, however the underlying molecular mechanisms remain unclear. Here, we identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis.
  
  
  METHODS
  To explore the role of Scrib during epidermal development, we compared the permeability of toluidine blue dye in wild-type, Scrib heterozygous and Scrib KO embryonic epidermis at E16.5, E17.5 and E18.5. Mouse embryos were stained with alcian blue and alizarin red for skeletal analysis. To establish whether Scrib plays a tumor suppressive role during skin tumorigenesis and/or progression, we evaluated an autochthonous mouse model of skin carcinogenesis in the context of Scrib loss. We utilised Cre-LoxP technology to conditionally deplete Scrib in adult epidermis, since Scrib KO embryos are neonatal lethal.
  
  
  RESULTS
  We establish that Scrib perturbs keratinocyte maturation during embryonic development, causing impaired epidermal barrier formation, and that Scrib is required for skeletal morphogenesis in mice. Analysis of conditional transgenic mice deficient for Scrib specifically within the epidermis revealed no skin pathologies, indicating that Scrib is dispensable for normal adult epidermal homeostasis. Nevertheless, bi-allelic loss of Scrib significantly enhanced tumor multiplicity and progression in an autochthonous model of epidermal carcinogenesis in vivo, demonstrating Scrib is an epidermal tumor suppressor. Mechanistically, we show that apoptosis is the critical effector of Scrib tumor suppressor activity during skin carcinogenesis and provide new insight into the function of polarity proteins during DNA damage repair.
  
  
  CONCLUSIONS
  For the first time, we provide genetic evidence of a unique link between skin carcinogenesis and loss of the epithelial polarity regulator Scrib, emphasizing that Scrib exerts a wide-spread tumor suppressive function in epithelia.
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia. Helen.Pearson@petermac.org.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia. Helen.Pearson@petermac.org.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: EMBL Australia, Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Edwina
authors.initials: E
authors.lastname: McGlinn
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.|Present address: Olivia Newton-John Cancer Research Institute and School of Cancer Medicine at La Trobe University, Heidelberg, VIC, 3084, Australia.
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Phesse
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.|Present address: National Center for Tumor Diseases Heidelberg (NCT), German Cancer Research Centre (DKFZ), 69120, Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schlüter
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: Anuratha
authors.initials: A
authors.lastname: Srikumar
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Gödde
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Woelwer
authors.affiliation: TissuPath Laboratories, Mount Waverley, VIC, 3149, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ryan
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.|Department of Surgery (St. Vincent's Hospital), The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.|Present address: Olivia Newton-John Cancer Research Institute and School of Cancer Medicine at La Trobe University, Heidelberg, VIC, 3084, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Pritinder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.|Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.|Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Humbert
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004817:Epidermis / Q000254:growth & development* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D016147:Genes, Tumor Suppressor; D006801:Humans; D019426:Integrases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019426:Integrases; D047908:Intracellular Signaling Peptides and Proteins; C508433:scrib protein, mouse; C045073:Cre recombinase