Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell line

Himelstein, Bruce P.; Lee, Edward J.; Sato, Hiroshi; Seiki, Motoharu; Muschel, Ruth J.

doi:10.1038/sj.onc.1201012

Cited by 100 publications

(75 citation statements)

References 17 publications

(21 reference statements)

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“…MMP-9 was low or undetectable in the C6 and C31 cells, as compared with 231/V cells, which secreted high levels of MMP-9 enzymatic activity (Figure 4c). MMP-9 is a metalloprotease that plays a role in the degradation of type IV collagen (gelatin), and has been found highly expressed in breast carcinomas (Himelstein et al, 1997). Our results strongly suggest that the enzymatic activity of MMP-9 is associated with HRG expression, and that both are involved in the invasive and metastatic phenotype of MDA-MB-231 cells.…”

supporting

confidence: 55%

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

et al. 2003

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The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorageindependent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.

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confidence: 55%

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

et al. 2003

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“…Although the precise mechanism by which they act is at present under question, it is possible they may act through the activation and/or release of bound growth factors or receptors (Fowlkes et al, 1995;Levi et al, 1996;Manes et al, 1997;Suzuki et al, 1997). It is clear that many MMPs are overexpressed in cancers through the action of oncogenes and growth factors which represent positive or stimulatory signals for expression (Mauviel, 1993;Himelstein et al, 1997). As such, MMPs regulated in this way represent a positive 'mode' of tumour progression, that is, a gain of function is required for expression.…”

Section: Discussionmentioning

confidence: 99%

‘Proteolytic switching’: opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression

et al. 1999

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Tumour progression is associated with the accumulation of genetic changes which can result in eventual acquisition of malignant properties, i.e. in the emergence of tumour cell populations that have acquired a sufficient number of properties to allow them to metastasize. In this regard, proteolytic degradation of the extracellular matrix is thought to play a crucial role in the liberation and seeding of cancer cells during the process of metastasis (StetlerStevenson et al, 1996). Furthermore, the family of matrix metalloproteinases (MMP) is likely to be responsible for much of the proteolytic degradation associated with tumour cell invasion. This is because members of this family have a wide substrate specificity, including type IV or basement membrane collagen, and are often associated with normal and disease processes in which turnover of matrix components is essential to the process (MacDougall and Matrisian, 1995). A role for the MMPs in metastasis is also supported by the fact that transfection of metastatic cancer cell populations with the gene that encodes the endogenous inhibitor of MMPs, tissue inhibitor of metalloproteinase (TIMP-1), markedly inhibits both experimental and spontaneous metastasis in a number of models (DeClerck et al, 1992). This regulatory role of TIMPs suggests that it is the net proteolytic balance between the production of enzymes and their inhibitors that determines the metastatic capacity of the cells (DeClerck and Imren, 1994).The MMP subfamily of the gelatinases, in particular, has been a focus of study since these enzymes have been shown to have the ability to degrade type IV collagen (Collier et al, 1988;Wilhelm et al, 1989), a property thought to be required by all cells crossing any basement membrane. Gelatinase B has been demonstrated, by transfection analysis, to confer metastatic competence upon nonmetastatic rat fibroblastic cells, thus implicating it as a possible key enzyme in the process of metastasis (Bernhard et al, 1994). The demonstration that gelatinase B is involved in tissue invasion of normal trophoblasts (Librach et al, 1991) and macrophages (Watanabe et al, 1993) also lends support to its role as an enzyme mediating invasiveness of both normal and malignant cells. Despite this information, however, little is known about the regulation of gelatinase B expression, and how it can become de-regulated during cancer progression. Studies have shown the gene which Summary Although it is generally accepted that proteolytic degradation is an important mechanism used by malignant cells in the process of metastasis, comparatively little is known about the regulation of molecules responsible for proteolysis and how they become de-regulated during human tumour progression. Using a genetically related pair of human melanoma cell lines, derived from the same patient at different stages of disease, we analysed differences in the cytokine-mediated regulation of gelatinase B (MMP-9), an enzyme thought to play an important role in cellular invasiveness, and TIMP-1, a physiologi...

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“…For example, prolonged activation of Erk-1 and Erk-2 is associated with continued expression and phosphorylation of the transcription factor, Ets-2 (40), which can promote MMP-9 expression in tumor cell lines (41). Activation of NFB and AP-1 also contribute to MMP-9 expression in tumor cells (42), as well as in primary cultured foreskin fibroblasts (43).…”

Section: Figmentioning

confidence: 99%

Nerve Growth Factor Activation of Erk-1 and Erk-2 Induces Matrix Metalloproteinase-9 Expression in Vascular Smooth Muscle Cells

Khan¹,

Falcone²,

Kraemer³

2002

Journal of Biological Chemistry

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In response to vascular injury, smooth muscle cells migrate from the media into the intima, where they contribute to the development of neointimal lesions. Increased matrix metalloproteinase (MMP) expression contributes to the migratory response of smooth muscle cells by releasing them from their surrounding extracellular matrix. MMPs may also participate in the remodeling of extracellular matrix in vascular lesions that could lead to plaque weakening and subsequent rupture. Neurotrophins and their receptors, the Trk family of receptor tyrosine kinases, are expressed in neointimal lesions, where they induce smooth muscle cell migration. We now report that nerve growth factor (NGF)-induced activation of the TrkA receptor tyrosine kinase induces MMP-9 expression in both primary cultured rat aortic smooth muscle cells and in a smooth muscle cell line genetically manipulated to express TrkA. The response to NGF was specific for MMP-9 expression, as the expression of MMP-2, MMP-3, or the tissue inhibitor of metalloproteinase-2 was not changed. Activation of the Shc/mitogen-activated protein kinase pathway mediates the induction of MMP-9 in response to NGF, as this response is abrogated in cells expressing a mutant TrkA receptor that does not bind Shc and by pretreatment of cells with the MEK-1 inhibitor, U0126. Thus, these results indicate that the neurotrophin/Trk receptor system, by virtue of its potent chemotactic activity for smooth muscle cells and its ability to induce MMP-9 expression, is a critical mediator in the remodeling that occurs in the vascular wall in response to injury.

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Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell line

Cited by 100 publications

References 17 publications

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

‘Proteolytic switching’: opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression

Nerve Growth Factor Activation of Erk-1 and Erk-2 Induces Matrix Metalloproteinase-9 Expression in Vascular Smooth Muscle Cells

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