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

70 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Breast
Growth
Mitogen-Activated Protein Kinase Kinases
Laminin
Neoplasms
Morphogenesis
Conditioned Culture Medium
Heterografts
Extracellular Matrix
Homeostasis
Epithelial Cells
Breast Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. / Beliveau, Alain; Mott, Joni D.; Lo, Alvin; Chen, Emily I.; Koller, Antonius A.; Yaswen, Paul; Muschler, John; Bissell, Mina J.

In: Genes and Development, Vol. 24, No. 24, 15.12.2010, p. 2800-2811.

Research output: Contribution to journalArticle

Beliveau, Alain ; Mott, Joni D. ; Lo, Alvin ; Chen, Emily I. ; Koller, Antonius A. ; Yaswen, Paul ; Muschler, John ; Bissell, Mina J. / Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. In: Genes and Development. 2010 ; Vol. 24, No. 24. pp. 2800-2811.
@article{b3d47609664d4a67bff96fe1a803b305,
title = "Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo",
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.",
keywords = "Breast cancer cells, MAPK, Matrix metalloproteinase9 (MMP9), Three-dimensional (3D) culture models, Tissue architecture",
author = "Alain Beliveau and Mott, {Joni D.} and Alvin Lo and Chen, {Emily I.} and Koller, {Antonius A.} and Paul Yaswen and John Muschler and Bissell, {Mina J.}",
year = "2010",
month = "12",
day = "15",
doi = "10.1101/gad.1990410",
language = "English (US)",
volume = "24",
pages = "2800--2811",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "24",

}

TY - JOUR

T1 - Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo

AU - Beliveau, Alain

AU - Mott, Joni D.

AU - Lo, Alvin

AU - Chen, Emily I.

AU - Koller, Antonius A.

AU - Yaswen, Paul

AU - Muschler, John

AU - Bissell, Mina J.

PY - 2010/12/15

Y1 - 2010/12/15

N2 - 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.

AB - 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.

KW - Breast cancer cells

KW - MAPK

KW - Matrix metalloproteinase9 (MMP9)

KW - Three-dimensional (3D) culture models

KW - Tissue architecture

UR - http://www.scopus.com/inward/record.url?scp=78650220991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650220991&partnerID=8YFLogxK

U2 - 10.1101/gad.1990410

DO - 10.1101/gad.1990410

M3 - Article

C2 - 21159820

AN - SCOPUS:78650220991

VL - 24

SP - 2800

EP - 2811

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 24

ER -