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PMID: 19041750 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.

Cell ·Vol. 135 ·No. 5 ·2008-11-28 ·Pages 865-78

Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK

Abstract

Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation. In mammals, the role that polarity proteins play during tumorigenesis is not well understood. Here, we demonstrate that depletion of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis, and induces dysplasia in vivo that progress to tumors after long latency. Loss of Scribble cooperates with oncogenes such as c-myc to transform epithelial cells and induce tumors in vivo by blocking activation of an apoptosis pathway. Like depletion, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation. Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble. Thus, we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.

MeSH Terms
Animals Apoptosis Breast Neoplasms/metabolism Cell Line, Tumor Cell Polarity Down-Regulation Epithelial Cells/cytology Humans Intracellular Signaling Peptides and Proteins/genetics Mammary Glands, Animal/cytology,metabolism Mammary Neoplasms, Animal/metabolism Membrane Proteins/genetics Mice Proto-Oncogene Proteins c-myc/metabolism Tumor Suppressor Proteins/genetics
Chemicals
Intracellular Signaling Peptides and Proteins Membrane Proteins Myc protein, mouse Proto-Oncogene Proteins c-myc SCRIB protein, human Tumor Suppressor Proteins scribble protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zhan Lixing
Cold Spring Harbor Laboratory, Watson School of Biological Sciences, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Rosenberg Avi
Bergami Kenneth C
Yu Min
Xuan Zhenyu
Jaffe Aron B
Allred Craig
Muthuswamy Senthil K
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2008.09.045
Published
2008-11-28
Pages
865-78
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3015046
Subset
IM
Grants
NCI NIH HHS · R56 CA098830-05A1 · United States
NCI NIH HHS · R01 CA098830 · United States
NCI NIH HHS · U01 CA105388 · United States
NCI NIH HHS · R56 CA098830 · United States
NCI NIH HHS · CA098830 · United States
NCI NIH HHS · CA105388 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2008.09.045 PMC Full Text View journal details
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