title: Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer.
abstract: Scribble (SCRIB) localizes to cell-cell junctions and regulates establishment of epithelial cell polarity. Loss of expression of SCRIB functions as a tumor suppressor in Drosophila and mammals; conversely, overexpression of SCRIB promotes epithelial differentiation in mammals. Here, we report that SCRIB is frequently amplified, mRNA overexpressed, and protein is mislocalized from cell-cell junctions in human breast cancers. High levels of SCRIB mRNA are associated with poor clinical prognosis, identifying an unexpected role for SCRIB in breast cancer. We find that transgenic mice expressing a SCRIB mutant [Pro 305 to Leu (P305L)] that fails to localize to cell-cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia that progresses to highly pleomorphic and poorly differentiated tumors with basal characteristics. SCRIB interacts with phosphatase and tensin homolog (PTEN) and the expression of P305L, but not wild-type SCRIB, promotes an increase in PTEN levels in the cytosol. Overexpression of P305L, but not wild-type SCRIB, activates the Akt/mTOR/S6K signaling pathway. Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA, identifying SCRIB amplification as a mechanism of activating PI3K signaling in tumors without mutations in PIK3CA or PTEN. Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway.
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Feigin
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: S Dipikaa
authors.initials: SD
authors.lastname: Akshinthala
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Muthuswamy
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Bernard
authors.initials: B
authors.lastname: Martin
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Authors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, TennesseeAuthors' Affiliations: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Princess Margaret Cancer Center, Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto; Ontario Institute for Cancer Research, Ontario, Canada; Center for Comparative Medicine, University of California, Davis, Davis, California; and Department of Biochemistry, Vanderbilt University, Nashville, Tennessee s.muthuswamy@utoronto.ca.
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Muthuswamy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D015870:Gene Expression / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C480591:SCRIB protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human