Matrix-metalloproteinases 1, 2 and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: an in situ hybridization study

Brummer, Oliver; Athar, Saima; Riethdorf, Lutz; Löning, Thomas; Herbst, Hermann

doi:10.1007/s004280050442

Cited by 102 publications

(80 citation statements)

References 28 publications

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“…Similar to ERK1/2, both MMPs and PAI-1 are expressed by tumour cells and stromal cells in varying proportions (Brummer et al, 1999;Dublin et al, 2000). In a prior study with the same cohort, expression of the active MMP1 enzyme was associated with ER positivity and a negative nodal status, whereas high MMP9 protein levels correlated with nodal involvement (Milde-Langosch et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

et al. 2005

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Extracellular-regulated kinases (ERK1, ERK2) play important roles in the malignant behaviour of breast cancer cells in vitro. In our present study, 148 clinical breast cancer samples (120 cases with follow-up data) were studied for the expression of ERK1, ERK2 and their phosphorylated forms p-ERK1 and p-ERK2 by immunoblotting, and p-ERK1/2 expression in corresponding paraffin sections was analysed by immunohistochemistry. The results were correlated with established clinical and histological prognostic parameters, follow-up data and expression of seven cell-cycle regulatory proteins as well as MMP1, MMP9, PAI-1 and AP-1 transcription factors, which had been analysed before. High p-ERK1 expression as determined by immunoblots correlated significantly with a low frequency of recurrences and infrequent fatal outcome (P ¼ 0.007 and 0.008) and was an independent indicator of long relapse-free and overall survival in multivariate analysis. By immunohistochemistry, strong p-ERK staining in tumour cells was associated with early stages (P ¼ 0.020), negative nodal status (P ¼ 0.003) and long recurrence-free survival (P ¼ 0.017). In contrast, expression of the unphosphorylated kinases ERK1 and ERK2 was not associated with clinical and histological prognostic parameters, except a positive correlation with oestrogen receptor status. Comparison with the expression of formerly analysed cell-cycle-and invasion-associated proteins corroborates our conclusion that activation of ERK1 and ERK2 is not associated with enhanced proliferation and invasion of mammary carcinomas. Growth factors or cytokines exert positive and negative effects on cell proliferation and differentiation. After binding to their membrane receptors, the message is relayed to the nucleus by a complex system of intracellular signalling pathways. The majority of signalling molecules involved in these pathways are kinases, which are themselves activated by phosphorylation and repressed by their specific phosphatases. The mitogen-activated protein kinase (MAPK) signalling pathway includes a cascade of four groups of kinases (MAPKKKKs, MAPKKKs, MAPKKs and MAPKs). The MAPK kinase kinase kinases of the first level are phosphorylated in response to various extracellular stimuli through interaction with small GTP-binding proteins like Ras, Raf, etc. The activated enzymes then phosphorylate one of 14 kinases of the second level (the MAPKKKs, that is, Raf proteins, MEKK1-4, etc.), which themselves activate one of the MAPK kinases (MEK1 and 2, MKK3 -7) of the third level. Finally, these kinases (MAPKKs) activate MAP kinases, which are then able to phosphorylate transcription factors, which regulate the expression of genes involved in cell proliferation or differentiation. Three different, partly interacting signalling pathways have been identified in mammalian cells, leading to the activation of three types of MAP kinases: the MAP kinase JNK (Jun kinase) phosphorylates c-Jun, JunB, ATF2 and ELK1, etc., P38 activates ATF2, ELK-1 and MAX, whereas ERK1 and ERK2 phosphorylate...

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Section: Discussionmentioning

confidence: 99%

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

et al. 2005

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“…This has followed observations that patterns of MMP over-expression do not always predict aggressive tumour behaviour in either human [19,26,27] or animal tumours [28], that enhanced expression of the MMP inhibitors TIMP-1 and TIMP-2 frequently associates with poor outcome or tumour recurrence [29,30] and that MMPs can degrade components of the plasmin generating system and produce angiostatin, suggesting potential roles for MMPs in the regulation of cellular fibrinolytic activity and in the down-regulation of tumour-associated angiogenesis [31][32][33][34][35][36][37][38].…”

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confidence: 66%

“…MMP-3 is expressed by benign and low stage tumours but its expression is frequently lost in association with aggressive, advanced stage, disease [26,27]. TIMP-1 and TIMP-2 over-expression associates with malignant breast tumour behaviour in vivo [29,30].…”

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confidence: 99%

Inhibition of human MDA‐MB‐231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen

Farina¹,

Tacconelli²,

Cappabianca³

et al. 2002

European Journal of Biochemistry

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Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-CysGly-Val-Pro-Asp-NH 2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.Keywords: angiostatin-like; invasion; laminin; matrix metalloproteinase-3; plasminogen.The transition from carcinoma in situ to invasive adenocarcinoma of the breast is a relevant index of malignant behaviour and is characterized by loss and fragmentation of the ductal basement membrane (BM) [1,2]. Invasive breast tumour behaviour is associated with matrix-degrading enzyme over-expression, considered to be responsible for the promotion of the proteolytic environment required for destabilization and fragmentation of the ductal BM [3][4][5][6][7][8][9]. The invasive process has been effectively modelled in vitro using a reconstituted BM matrix prepared from mouse Engelbreath-Holm-Schwarm (EHS) sarcoma [10][11][12][13][14][15][16].A general concept is that a proteolytic cascade involving matrix metalloproteinases (MMPs) and the plasmin system degrades BM structures as a prerequisite for tumour cell invasion [17][18][19]. Plasmin activated from plasminogen by urokinase and tissue type plasminogen activators (uPA and t-PA, respectively) amplified at the tumour cell or matrix surface, degrades BM components and activates MMPs resulting in further amplification of BM degradation [17][18][19][20][21]. Amongst the MMP family, MMP-3 (stromelysin-1) is considered pivotal to the integration of plasmin and MMP systems, as it is highly sensitive to activation by plasmin and activates several MMPs. In addition, MMP-3 exhibits substrate specificity for BM components and has been implicated directly in both tumorigenesis and tumour invasion in vivo [19,[22][23][24].Recently, however, there has been a change in opinion about the potential roles played by ...

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“…In fact, it is currently known that in addition to their production by epithelial tumor cells, MMPs and/or TIMPs expression may be induced in infiltrating stromal fibroblasts and/or in vascular and inflammatory cells [68,71,75,121]. Therefore, the main source of MMPs in breast carcinoma are the stromal cells [122][123][124][125], and also experimental studies have demonstrated that the mechanism by which breast cancer cells can rapidly use MMPs produced by adjacent normal fibroblasts to facilitate their invasion into the peritumoral tissue [126].…”

Section: Mmps and Timps In Stromamentioning

confidence: 99%

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

2013

J Carcinog Mutagen

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Degradation of the stromal connective tissue and basement membrane components are key elements in tumor invasion and metastasis. Some components, particularly the interstitial collagens, are very resistant to proteolytic attacks and can be degraded by specific proteinases like Matrix Metalloproteinases (MMPs). MMPs can also impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, or chemokines/cytokines, and for stimulating angiogenesis. Different molecular expression profiles of MMPs and their inhibitors (TIMPs) have been associated with the main steps in breast cancer progression, such as creating a potential invasive phenotype in Ductal Carcinoma in situ (DCIS), favoring the hematogenous dissemination, and enabling the metastatic progression across the axillary lymphatic system. These associations have clinical interests, as they can contribute to a better characterization of early breast carcinomas (which differ in their both biological and clinical behavior), evaluate microinvasion in resection specimens of breast tumors, provide a more precise prognostic, and predict the tumoral status of non-sentinel lymph nodes in breast cancer. It is also especially remarkable the evidences indicating that MMPs and TIMPs expression in individual cell populations from tumor stroma, such as mononuclear inflammatory cells (MICs) and fibroblast, clearly impacts on the clinical outcome of breast cancer patients. There are several factors linking inflammation, MMP activity and breast cancer. This knowledge will be useful to develop novel therapies and prevention strategies targeting critical components.

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Matrix-metalloproteinases 1, 2 and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: an in situ hybridization study

Cited by 102 publications

References 28 publications

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

Inhibition of human MDA‐MB‐231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

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