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

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 in¯uence 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-de®cient 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.

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

“…Recent reports suggest that chronic stimulation of ROS upregulates at least four MMPs (MMP-2, MMP-3 and MMP-9, MMP-13), causing tumor initiation and dissemination (Mori et al, 2004). It has also been reported that MMP-3 and MMP-13 serve as tumor promoters (Sternlicht et al, 2000;Impola et al, 2005). These reports thus support our findings that overexpression of TCTP triggers ROS generation (Figure 4a), and upregulates MMP-3 and MMP-13 in MCF10A cells (Figure 5c).…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…Moreover, many genes are expressed and seem to be functional only during the metastatic process. Even more impressive, transgenic expression of MMP3 is sufficient to induce full-blown carcinogenesis, indicating that 'invasive or metastatic' processes can even affect the transformation status of a cell [132]. More refined approaches of gene expression analysis combined with functional experiments have now provided novel insights into such events.…”

EMT tumorigenesis in the mouse mammary gland

“…20 Cohort 6: tumors arise in FVB/N Tg(MMP-3/stromelysin-1) mice. 21 Cohort 7: tumors arise in FVB/N Tac-Tg(Hba-x-vHa-ras) TG-ACLed . 22 Immunohistochemistry and Immunofluorescence Four-micrometer-thick paraffin sections were stained with Mayer's H&E or immunostained as described previously.…”