Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability

Derek C. Radisky (), Dinah D. Levy, Laurie E. Littlepage, Hong Liu, Celeste M. Nelson, Jimmie E. Fata, Devin Leake, Elizabeth L. Godden, Donna G. Albertson, M. Angela Nieto, Zena Werb and Mina J. Bissell ()
Additional contact information
Derek C. Radisky: Lawrence Berkeley National Laboratory
Dinah D. Levy: Lawrence Berkeley National Laboratory
Laurie E. Littlepage: University of California
Hong Liu: Lawrence Berkeley National Laboratory
Celeste M. Nelson: Lawrence Berkeley National Laboratory
Jimmie E. Fata: Lawrence Berkeley National Laboratory
Devin Leake: Dharmacon Inc.
Elizabeth L. Godden: Dharmacon Inc.
Donna G. Albertson: University of California
M. Angela Nieto: Instituto de Neurociencias de Alicante
Zena Werb: University of California
Mina J. Bissell: Lawrence Berkeley National Laboratory

Nature, 2005, vol. 436, issue 7047, 123-127

Abstract: Abstract The tumour microenvironment can be a potent carcinogen, not only by facilitating cancer progression and activating dormant cancer cells, but also by stimulating tumour formation1. We have previously investigated stromelysin-1/matrix metalloproteinase-3 (MMP-3), a stromal enzyme upregulated in many breast tumours2, and found that MMP-3 can cause epithelial–mesenchymal transition (EMT) and malignant transformation in cultured cells3,4,5, and genomically unstable mammary carcinomas in transgenic mice3. 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.

Date: 2005
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/nature03688 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:436:y:2005:i:7047:d:10.1038_nature03688

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature03688

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().