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, Mina J. Bissell

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)123-127
Number of pages5
JournalNature
Volume436
Issue number7047
DOIs
StatePublished - Jul 7 2005
Externally publishedYes

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Matrix Metalloproteinase 3
Epithelial-Mesenchymal Transition
Genomic Instability
Reactive Oxygen Species
Tumor Microenvironment
Breast Neoplasms
Neoplasms
Cellular Structures
Carcinogens
Transgenic Mice
DNA Damage
Cultured Cells
Breast
Epithelial Cells
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., Fata, J. E., ... Bissell, M. J. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436(7047), 123-127. https://doi.org/10.1038/nature03688

Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. / Radisky, Derek C; Levy, Dinah D.; Littlepage, Laurie E.; Liu, Hong; Nelson, Celeste M.; Fata, Jimmie E.; Leake, Devin; Godden, Elizabeth L.; Albertson, Donna G.; Nieto, M. Angela; Werb, Zena; Bissell, Mina J.

In: Nature, Vol. 436, No. 7047, 07.07.2005, p. 123-127.

Research output: Contribution to journalArticle

Radisky, DC, Levy, DD, Littlepage, LE, Liu, H, Nelson, CM, Fata, JE, Leake, D, Godden, EL, Albertson, DG, Nieto, MA, Werb, Z & Bissell, MJ 2005, 'Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability', Nature, vol. 436, no. 7047, pp. 123-127. https://doi.org/10.1038/nature03688
Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005 Jul 7;436(7047):123-127. https://doi.org/10.1038/nature03688
Radisky, Derek C ; Levy, Dinah D. ; Littlepage, Laurie E. ; Liu, Hong ; Nelson, Celeste M. ; Fata, Jimmie E. ; Leake, Devin ; Godden, Elizabeth L. ; Albertson, Donna G. ; Nieto, M. Angela ; Werb, Zena ; Bissell, Mina J. / Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. In: Nature. 2005 ; Vol. 436, No. 7047. pp. 123-127.
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