Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo

Alain Beliveau, Joni D. Mott, Alvin Lo, Emily I. Chen, Antonius A. Koller, Paul Yaswen, John Muschler, Mina J. Bissell

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Organization into polarized three-dimensional structures defines whether epithelial cells are normal or malignant. In a model of morphogenesis, we show that inhibiting key signaling pathways in human breast cancer cells leads to "phenotypic reversion" of the malignant cells. Using architecture as an endpoint, we report that, in all cases, signaling through Raf/MEK/ERK disrupted tissue polarity via matrix metalloproteinase9 (MMP9) activity. Induction of Raf or activation of an engineered, functionally inducible MMP9 in nonmalignant cells led to loss of tissue polarity, and reinitiated proliferation. Conversely, inhibition of Raf or MMP9 with small molecule inhibitors or shRNAs restored the ability of cancer cells to form polarized quiescent structures. Silencing MMP9 expression also reduced tumor growth dramatically in a murine xenograft model. LC-MS/MS analysis comparing conditioned medium from nonmalignant cells with or without active MMP9 revealed laminin 111 (LM1) as an important target of MMP9. LM1 has been implicated in acinar morphogenesis; thus, its degradation by MMP9 provides a mechanism for loss of tissue polarity and reinitiation of growth associated with MMP9 activity. These findings underscore the importance of the dynamic reciprocity between the extracellular matrix integrity, tissue polarity, and Raf/MEK/ERK and MMP9 activities, providing an axis for either tissue homeostasis or malignant progression.

Original languageEnglish (US)
Pages (from-to)2800-2811
Number of pages12
JournalGenes and Development
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2010

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Keywords

  • Breast cancer cells
  • MAPK
  • Matrix metalloproteinase9 (MMP9)
  • Three-dimensional (3D) culture models
  • Tissue architecture

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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