PMID- 16001073
OWN - NLM
STAT- MEDLINE
DCOM- 20050719
LR  - 20220410
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 436
IP  - 7047
DP  - 2005 Jul 7
TI  - Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic 
      instability.
PG  - 123-7
AB  - The tumour microenvironment can be a potent carcinogen, not only by facilitating 
      cancer progression and activating dormant cancer cells, but also by stimulating 
      tumour formation. We have previously investigated stromelysin-1/matrix 
      metalloproteinase-3 (MMP-3), a stromal enzyme upregulated in many breast tumours, 
      and found that MMP-3 can cause epithelial-mesenchymal transition (EMT) and 
      malignant transformation in cultured cells, and genomically unstable mammary 
      carcinomas in transgenic mice. Here we explain the molecular pathways by which 
      MMP-3 exerts these effects: exposure of mouse mammary epithelial cells to MMP-3 
      induces the expression of an alternatively spliced form of Rac1, which causes an 
      increase in cellular reactive oxygen species (ROS). The ROS stimulate the 
      expression of the transcription factor Snail and EMT, and cause oxidative damage 
      to DNA and genomic instability. These findings identify a previously undescribed 
      pathway in which a component of the breast tumour microenvironment alters 
      cellular structure in culture and tissue structure in vivo, leading to malignant 
      transformation.
FAU - Radisky, Derek C
AU  - Radisky DC
AD  - Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, 
      California 94720, USA. dcradisky@lbl.gov
FAU - Levy, Dinah D
AU  - Levy DD
FAU - Littlepage, Laurie E
AU  - Littlepage LE
FAU - Liu, Hong
AU  - Liu H
FAU - Nelson, Celeste M
AU  - Nelson CM
FAU - Fata, Jimmie E
AU  - Fata JE
FAU - Leake, Devin
AU  - Leake D
FAU - Godden, Elizabeth L
AU  - Godden EL
FAU - Albertson, Donna G
AU  - Albertson DG
FAU - Nieto, M Angela
AU  - Nieto MA
FAU - Werb, Zena
AU  - Werb Z
FAU - Bissell, Mina J
AU  - Bissell MJ
LA  - eng
GR  - R01 CA057621/CA/NCI NIH HHS/United States
GR  - R01 CA057621-07/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Alternative Splicing/genetics
MH  - Animals
MH  - *Cell Differentiation
MH  - Cell Line
MH  - Cell Transformation, Neoplastic
MH  - DNA Damage
MH  - Epithelial Cells/cytology/enzymology/*metabolism
MH  - Genomic Instability/*genetics
MH  - Humans
MH  - Matrix Metalloproteinase 3/genetics/*metabolism
MH  - Mesoderm/cytology/enzymology/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitochondria/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Reactive Oxygen Species/*metabolism
MH  - rac1 GTP-Binding Protein/genetics/*metabolism
MH  - rho GTP-Binding Proteins/metabolism
PMC - PMC2784913
MID - NIHMS158447
EDAT- 2005/07/08 09:00
MHDA- 2005/07/20 09:00
PMCR- 2009/11/29
CRDT- 2005/07/08 09:00
PHST- 2005/02/22 00:00 [received]
PHST- 2005/04/25 00:00 [accepted]
PHST- 2005/07/08 09:00 [pubmed]
PHST- 2005/07/20 09:00 [medline]
PHST- 2005/07/08 09:00 [entrez]
PHST- 2009/11/29 00:00 [pmc-release]
AID - nature03688 [pii]
AID - 10.1038/nature03688 [doi]
PST - ppublish
SO  - Nature. 2005 Jul 7;436(7047):123-7. doi: 10.1038/nature03688.