Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability.
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.
Radisky
Derek C
DC
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. dcradisky@lbl.gov
Levy
Dinah D
DD
Littlepage
Laurie E
LE
Liu
Hong
H
Nelson
Celeste M
CM
Fata
Jimmie E
JE
Leake
Devin
D
Godden
Elizabeth L
EL
Albertson
Donna G
DG
Nieto
M Angela
MA
Werb
Zena
Z
Bissell
Mina J
MJ
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019278:Matrix Metalloproteinase 3; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins