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The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

Oncogene volume 19, pages 1102–1113 (2000)Cite this article

Abstract

Extracellular matrix-degrading matrix metalloproteinases (MMPs) are invariably upregulated in epithelial cancers and are key agonists in angiogenesis, invasion and metastasis. Yet most MMPs are secreted not by the cancer cells themselves, but by stromal cells within and around the tumor mass. Because the stromal environment can influence tumor formation, and because MMPs can alter this environment, MMPs may also contribute to the initial stages of cancer development. Several recent studies in MMP-overexpressing and MMP-deficient mice support this possibility, but have required carcinogens or pre-existing oncogenic mutations to initiate tumorigenesis. Here we review the spontaneous development of premalignant and malignant lesions in the mammary glands of transgenic mice that express an autoactivating form of MMP-3/stromelysin-1 under the control of the whey acidic protein gene promoter. These changes were absent in nontransgenic littermates and were quenched by co-expression of a human tissue inhibitor of metalloproteinases-1 (TIMP-1) transgene. Thus by altering the cellular microenvironment, stromelysin-1 can act as a natural tumor promoter and enhance cancer susceptibility.

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Acknowledgements

We thank R Boudreau, J Xie, DR Williams, and Drs CJ Sympson, A McMillan and RD Cardiff for their assistance. This work was supported by grants from the National Cancer Institute (CA57621 and CA72006), the US Army Medical Research and Materiel Command (DAMD17-97-1-7246), and the US Department of Energy, Office of Health and Environmental Research (DE-AC03-76-SF00098).

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  1. Department of Anatomy, University of California, 513 Parnassus Avenue, HSW-1301, San Francisco, 94143-0452, California, CA, USA

    Mark D Sternlicht & Zena Werb

  2. Life Sciences Division, Lawrence Berkeley National Laboratory, 94720, California, CA, USA

    Mina J Bissell

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Sternlicht, M., Bissell, M. & Werb, Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 19, 1102–1113 (2000). https://doi.org/10.1038/sj.onc.1203347

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