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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Mina J., 2005. "Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability," Nature, Nature, vol. 436(7047), pages 123-127, July.
    • Handle: RePEc:nat:nature:v:436:y:2005:i:7047:d:10.1038_nature03688
    DOI: 10.1038/nature03688
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    Cited by:

    1. Krishnaveni M, 2017. "Epithelial Mesenchymal Transition as Targets for Cancer Therapy," Novel Approaches in Drug Designing & Development, Juniper Publishers Inc., vol. 3(1), pages 14-18, November.

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