Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma

Lixing Zhan, Avi Rosenberg, Kenneth C. Bergami, Min Yu, Zhenyu Xuan, Aron B. Jaffe, Craig Allred, Senthil K. Muthuswamy

Research output: Contribution to journalArticle

282 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)865-878
Number of pages14
JournalCell
Volume135
Issue number5
DOIs
StatePublished - Nov 28 2008
Externally publishedYes

Keywords

  • CELLBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhan, L., Rosenberg, A., Bergami, K. C., Yu, M., Xuan, Z., Jaffe, A. B., Allred, C., & Muthuswamy, S. K. (2008). Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma. Cell, 135(5), 865-878. https://doi.org/10.1016/j.cell.2008.09.045