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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 5/2007

01-09-2007 | Research Paper

MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2

Authors: Odete Mendes, Hun-Taek Kim, Gina Lungu, George Stoica

Published in: Clinical & Experimental Metastasis | Issue 5/2007

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Abstract

Matrix metalloproteinase 2 (MMP2) is important in breast cancer (BC) invasion and metastasis. We previously reported that BC brain metastases, in a rat syngeneic model developed in our laboratory, have high expression and activity of MMP2. The MMP2 mechanism of action in the brain is still under intense scrutiny. To study the role of MMP2 in the development of BC brain metastasis we transfected ENU1564 rat mammary adenocarcinoma cells with tissue inhibitor of MMP2 (TIMP2). Animals inoculated with ENU1564-TIMP2 cells had decreased orthotopic tumor growth, decreased orthotopic metastastic behavior and did not develop brain metastases. These results were associated with decreased MMP2 activity, demonstrated by gel zymography. Mitogen activated protein kinase (MAPK) pathway components, such as ERK1/2, have been correlated to MMP expression and/or astrocyte activity. We found that BC brain metastases have peripheral astrocyte reactivity and higher expression of glial fibrillary acidic protein (GFAP) and phosphorylated-ERK1/2 (p-ERK1/2). Additionally, rat astrocyte-conditioned media increased in vitro invasion of ENU1564 cancer cells and increased expression of MMP2 and p-ERK1/2. Blockage of ERK1/2 phosphorylation by treatment with MEK inhibitor (PD98059) decreased the expression of MMP2 in cancer cells grown in rat astrocyte-conditioned media. Our results are highly suggestive that MMP2 plays a role in the development of BC metastases, in particular to the brain. Furthermore, our results suggest that astrocyte factors and the ERK1/2 signaling pathway may be associated with BC brain metastasis development; and that ERK1/2 may regulate MMP2 in a way that is modifiable by astrocyte factors.
Literature
1.
Nishizuka I, Ishikawa T et al (2002) Analysis of gene expression involved in brain metastases from breast cancer using cDNA microarray. Breast Cancer 9(1):26–32PubMedCrossRef
2.
Jaalinoja J, Herva R et al (2000) Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms. J Neurooncol 46(1):81–90PubMedCrossRef
3.
Arnold SM, Young AB et al (1999) Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastases. Clin Cancer Res 5(12):4028–4033PubMed
4.
Mendes O, Kim HT, Stoica G (2005) Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis 22(3):237–246PubMedCrossRef
5.
Hall DG, Stoica G (1994) Characterization of brain and bone-metastasizing clones selected from an ethylnitrosurea-induced rat mammary carcinoma. Clin Exp Metastasis 12(4):283–295PubMedCrossRef
6.
Leppa S, Saarto T, Vehmanen L et al (2004) High serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma. Clin Cancer Res 10(3):1057–1063PubMedCrossRef
7.
Duffy MJ, Maguire TM et al (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastases. Breast Cancer Res 2(4):252–257 (Epub 2000 Jun 7)PubMedCrossRef
8.
Danilewicz M, Sikorska B, Wagrowska-Danilewicz M (2003) Prognostic significance of the immunoexpression of matrix metalloproteinase MMP2 and its inhibitor TIMP2 in laryngeal cancer. Med Sci Monit 9(3):MT42–MT47PubMed
9.
Kazes I, Elalamy I, Sraer JD et al (2000) Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. Blood 96(9):3064–3069PubMed
10.
Gakiopoulou H, Nakopoulou L, Siatelis A et al (2003) Tissue inhibitor of metalloproteinase-2 as a multifunctional molecule of which the expression is associated with adverse prognosis of patients with urothelial bladder carcinomas. Clin Cancer Res 9(15):5573–5581PubMed
11.
Remacle A, McCarthy K, Noel A et al (2000) High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer 89(2):118–121PubMedCrossRef
12.
Visscher DW, Hoyhtya M, Ottosen SK et al (1994) Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer 59(3):339–344PubMedCrossRef
13.
Zhao YG, Xiao AZ, Park HI et al (2004) Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion. Cancer Res 64(2):590–598PubMedCrossRef
14.
Li H, Lindenmeyer F, Grenet C et al (2001) AdTIMP-2 inhibits tumor growth, angiogenesis, and metastases, and prolongs survival in mice. Hum Gene Ther 12(5):515–526PubMedCrossRef
15.
Liuzzi GM, Mastroianni CM, Latronico T et al (2004) Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia. Brain 127(Pt 2):398–407 (Epub 2003 Dec 8)PubMedCrossRef
16.
Massengale JL, Gasche Y, Chan PH (2002) Carbohydrate source influences gelatinase production by mouse astrocytes in vitro. Glia 38(3):240–245PubMedCrossRef
17.
Rosenberg GA, Cunningham LA, Wallace J et al (2001) Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 893(1–2):104–112PubMedCrossRef
18.
Giraudon P, Szymocha R, Buart S et al (2000) T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: relevance to HTLV-I-induced neurological disease. J Immunol 164(5):2718–2727PubMed
19.
Nagashima G, Suzuki R, Asai J et al (2002) Immunohistochemical analysis of reactive astrocytes around glioblastoma: an immunohistochemical study of postmortem glioblastoma cases. Clin Neurol Neurosurg 104(2):125–131PubMedCrossRef
20.
Levicar N, Nuttall RK, Lah TT (2003) Proteases in brain tumour progression. Acta Neurochir (Wien) 145(9):825–838CrossRef
21.
Nuttall RK, Pennington CJ, Taplin J et al (2003) Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res 1(5):333–345PubMed
22.
Le DM, Besson A, Fogg DK et al (2003) Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J Neurosci 23(10):4034–4043PubMed
23.
Leveque T, Le Pavec G, Boutet A et al (2004) Differential regulation of gelatinase A and B and TIMP-1 and -2 by TNFalpha and HIV virions in astrocytes. Microbes Infect 6(2):157–163PubMedCrossRef
24.
Muir EM, Adcock KH, Morgenstern DA et al (2002) Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes. Brain Res Mol Brain Res 100(1–2):103–117PubMedCrossRef
25.
Arai K, Lee SR, Lo EH (2004) Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase-9 regulation in rat cortical astrocytes. Glia 43(3):254–264CrossRef
26.
Lee WJ, Shin CY, Yoo BK et al (2003) Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2). Glia 41(1):15–24PubMedCrossRef
27.
Sierra A, Price JE, Garcia-Ramirez M et al (1997) Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest 77(4):357–368PubMed
28.
Alessandrini A (2002) The roles of map kinases in controlling cancer metastases. In: Welch DR (ed) Cancer metastases-related genes, vol 3. Kluwer, Boston, pp 35–51CrossRef
29.
Christopherson KS, Ullian EM, Stokes CC et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433PubMedCrossRef
30.
Venugopal SK, Devaraj S, Jialal I (2005) Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: potential for paracrine/autocrine effects. Am J Pathol 166(4):1265–1271PubMed
31.
Lu W, Zhou X, Hong B et al (2004) Suppression of invasion in human U87 glioma cells by adenovirus-mediated co-transfer of TIMP-2 and PTEN gene. Cancer Lett 214(2):205–213PubMedCrossRef
32.
Forough R, Lea H, Starcher B et al (1998) Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima. Arterioscler Thromb Vasc Biol 18(5):803–807PubMed
33.
Kai HS, Butler GS, Morrison CJ et al (2002) Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain. J Biol Chem 277(50):48696–48707 (Epub 2002 Oct 8)PubMedCrossRef
34.
Lee PP, Hwang JJ, Murphy G et al (2000) Functional significance of MMP-9 in tumor necrosis factor-induced proliferation and branching morphogenesis of mammary epithelial cells. Endocrinology 141(10):3764–3773PubMedCrossRef
35.
Scott KA, Holdsworth H, Balkwill FR et al (2000) Exploiting changes in the tumour microenvironment with sequential cytokine and matrix metalloprotease inhibitor treatment in a murine breast cancer model. Br J Cancer 83(11):1538–1543PubMedCrossRef
36.
Tester AM, Waltham M, Oh SJ et al (2004) Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastases of MDA-MB-231 human breast cancer cells in nude mice. Cancer Res 64(2):652–658PubMedCrossRef
37.
Hanemaaijer R, Verheijen JH, Maguire TM et al (2000) Increased gelatinase-A and gelatinase-B activities in malignant vs. benign breast tumors. Int J Cancer 86(2):204–207PubMedCrossRef
38.
Xie TX, Huang FJ, Aldape KD et al (2006) Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res 66(6):3188–3196PubMedCrossRef
39.
Yoneda T (2000) Cellular and molecular basis of preferential metastases of breast cancer to bone. J Orthop Sci 5(1):75–81PubMedCrossRef
40.
Rolli M, Fransvea E, Pilch J et al (2003) Activated integrin alphavbeta3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc Natl Acad Sci USA 100(16):9482–9487 (Epub 2003 Jul 21)PubMedCrossRef
41.
Saad S, Bendall LJ, James A et al (2000) Induction of matrix metalloproteinases MMP-1 and MMP-2 by co-culture of breast cancer cells and bone marrow fibroblasts. Breast Cancer Res Treat 63(2):105–115PubMedCrossRef
42.
Wang M, Liu YE, Greene J et al (1997) Inhibition of tumor growth and metastases of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14(23):2767–2774PubMedCrossRef
43.
Thorgeirsson UP, Yoshiji H et al (1996) Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis. In Vivo 10(2):137–144PubMed
44.
Kawamata H, Kawai K, Kameyama S et al (1995) Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastases of a rat bladder carcinoma. Int J Cancer 63(5):680–687PubMedCrossRef
45.
Ahn SM, Jeong SJ, Kim YS et al (2004) Retroviral delivery of TIMP-2 inhibits H-RAS-induced migration and invasion in MCF10A human breast epithelial cells. Cancer Lett 207(1):49–57PubMedCrossRef
46.
Kim MS, Lee EJ, Kim HR et al (2003) p38 kinase is a key signaling molecule for H-RAS-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 63(17):5454–5461PubMed
47.
Liu JF, Crepin M, Liu JM et al (2002) FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the RAS/ERK pathway. Biochem Biophys Res Commun 293(4):1174–1182PubMedCrossRef
48.
Pan MR, Hung WC (2002) Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. J Biol Chem 277(36):32775–32780 (Epub 2002 Jun 26)PubMedCrossRef
49.
Tanimura S, Asato K, Fujishiro SH et al (2003) Specific blockade of the ERK pathway inhibits the invasiveness of tumor cells: down-regulation of matrix metalloproteinase-3/-9/-14 and CD44. Biochem Biophys Res Commun 304(4):801–806PubMedCrossRef
50.
Fromigue O, Louis K, Wu E et al (2003) Active stromelysin-3 (MMP-11) increases MCF-7 survival in three-dimensional Matrigel culture via activation of p42/p44 MAP-kinase. Int J Cancer 106(3):355–363PubMedCrossRef
51.
Utani A, Momota Y, Endo H et al (2003) Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling. J Biol Chem 278(36):34483–34490 (Epub 2003 Jun 24)PubMedCrossRef
Metadata
Title
MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2
Authors
Odete Mendes
Hun-Taek Kim
Gina Lungu
George Stoica
Publication date
01-09-2007
Publisher
Kluwer Academic Publishers
Published in
Clinical & Experimental Metastasis / Issue 5/2007
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-007-9071-0

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