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Erschienen in: Journal of Mammary Gland Biology and Neoplasia 2/2010

Open Access 01.06.2010

Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer

verfasst von: Evette S. Radisky, Derek C. Radisky

Erschienen in: Journal of Mammary Gland Biology and Neoplasia | Ausgabe 2/2010

Abstract

Matrix metalloproteinases (MMPs) degrade and modify the extracellular matrix (ECM) as well as cell-ECM and cell-cell contacts, facilitating detachment of epithelial cells from the surrounding tissue. MMPs play key functions in embryonic development and mammary gland branching morphogenesis, but they are also upregulated in breast cancer, where they stimulate tumorigenesis, cancer cell invasion and metastasis. MMPs have been investigated as potential targets for cancer therapy, but clinical trials using broad-spectrum MMP inhibitors yielded disappointing results, due in part to lack of specificity toward individual MMPs and specific stages of tumor development. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells take on the characteristics of invasive mesenchymal cells, and activation of EMT has been implicated in tumor progression. Recent findings have implicated MMPs as promoters and mediators of developmental and pathogenic EMT processes in the breast. In this review, we will summarize recent studies showing how MMPs activate EMT in mammary gland development and in breast cancer, and how MMPs mediate breast cancer cell motility, invasion, and EMT-driven breast cancer progression. We also suggest approaches to inhibit these MMP-mediated malignant processes for therapeutic benefit.
Abkürzungen
EMT
epithelial-mesenchymal transition
MMP
matrix metalloproteinase
ECM
extracellular matrix
TIMP
tissue inhibitor of metalloproteinase
PEX
hemopexin
TGF-β
transforming growth factor-β
LRP
lipoprotein receptor-related protein
WAP
whey acidic protein
MMTV
mouse mammary tumor virus
PyMT
polyoma virus middle T-antigen

Matrix Metalloproteinases: Overview

There are 23 human MMPs (Degradome database; http://​degradome.​uniovi.​es) [1], including 17 soluble, secreted enzymes and 6 membrane-associated enzymes (Fig. 1); they differ from each other in their structural domain architecture, in their substrate specificity, and in their temporal and tissue specific expression patterns. MMPs were originally named for their preferred substrates within the extracellular matrix (ECM): collagen-cleaving MMPs (MMP-1, -8, and -13) were designated collagenases, gelatin (denatured collagen)-cleaving MMPs (MMP-2 and -9) were termed gelatinases, and MMPs that degraded a broad spectrum of ECM proteins were called stromelysins (MMP-3, -10, and -11) or matrilysins (MMP-7). As the MMP family grew with the discovery of additional paralogs, including the membrane-associated MMPs, of which MT1-MMP/MMP-14 is the founding member, a numbering system was adopted, and MMPs are now grouped according to their domain structure.
MMPs are modular enzymes (Fig. 1a). The core functional domain of every MMP is the catalytic domain, a compact globular domain of 160–170 amino acids featuring a highly conserved HExxHxxGxxH zinc binding motif, responsible for chelating the catalytically essential zinc ion at the enzyme active site [2]. The catalytic zinc and substrate binding cleft of the catalytic domain comprise the MMP region targeted for binding and inhibition by the endogenous tissue inhibitors of metalloproteinases (TIMPs) [3], and also by the majority of small-molecule, synthetic pharmaceutical inhibitors of MMPs [4]. MMPs are produced as latent proenzymes, in which an N-terminal prodomain of ∼80 amino acids blocks catalytic activity by physically blocking the active site, through coordination of a conserved cysteine residue within a PRCGxPD motif (“the cysteine switch”) to the catalytic zinc [2, 5]. Upon stepwise interaction with and cleavage by one or more activating proteases [5, 6], the cleaved MMP prodomain dissociates from the catalytic domain, releasing the active enzyme.
Most MMPs also possess additional accessory domains that act to modulate catalytic activity, substrate recognition, and cellular localization [3, 7]; some accessory domains may also confer non-catalytic functions of potential significance for understanding MMP roles in EMT and tumor progression. The gelatinases MMP-2 and -9 are assisted in substrate binding of gelatin, collagens, and laminin by three fibronectin repeats inserted into the catalytic domain [8]. All human MMPs with the exception of MMP-7, -23, and -26A possess a C-terminal hemopexin (PEX) domain, a four-bladed propeller structure that is connected to the catalytic domain by a flexible linker [9, 10]. PEX domains have been shown to mediate the binding and unwinding of collagen triple helices by collagenases, facilitating cleavage by the MMP catalytic domain [1114], as well as the recognition of other substrates including gelatin binding by MMP-9 [15], fibrinogen binding by MMP-2 [16], and targeting of several chemokines by MMP-2 [1719]. Beyond substrate recognition, PEX domains can mediate interactions with tissue inhibitors of metalloproteinases (TIMPs), with distinctly different results for different MMP/TIMP pairs: proMMP-2 is targeted for MT1-MMP-mediated activation by TIMP-2 [3, 5], while proMMP-9, by binding to TIMP-1, is protected from activation [2022].
In mammary epithelial cells, specific interactions between PEX domains and integrins or other cell surface receptors have been found to facilitate MMP activation, to localize soluble MMPs to sites of pericellular proteolysis, or to regulate MMP endocytosis and turnover [10]. MMP-9 docking to the hyaluronan receptor CD44 mediates proteolytic activation of TGF-β and promotion of tumor invasion and angiogenesis in a murine mammary carcinoma model [23]. Association of the MT1-MMP PEX domain with CD44H leads to localization of MT1-MMP at the leading edge of migrating cells [24] and facilitates cell migration [25]. Interaction between MT1-MMP and CD44 also stimulated epithelial cell self-sorting in an engineered model of mammary ductal morphogenesis; this function did not appear to depend upon MMP catalytic activity [26].

MMPs Stimulate Breast Cancer Progression

While a finely tuned array of MMPs is instrumental in orchestrating tissue development and homeostasis, the misregulation of MMPs is widespread in many pathological settings and especially in cancer, where MMP overexpression contributes to tumorigenesis and tumor progression through multiple mechanisms. MMP proteolysis serves a path-clearing role in facilitating the movement of cells or groups of cells through ECM [27, 28]; in this process, cleavage of some ECM components unmasks cryptic sites, generating fragments with new biological activities modulating migration, growth, or angiogenesis [27, 28]. MMPs also cleave cell-ECM adhesion proteins and cell-cell junction proteins, releasing individual epithelial cells from epithelial sheets, initiating outside-in signaling pathways that lead to widespread changes in gene transcription patterns, or generating soluble ectodomain fragments with novel activities. MMP-1 cleaves and activates the protease activated receptor-1 (PAR-1), leading to increased migration and invasion of breast cancer cells [29]. Targeting of E-cadherin by MMP-3 or MMP-7 generates a bioactive fragment that promotes invasion [30], and contributes to a cascade of molecular alterations leading to EMT in mammary epithelial cells [30, 31]. MT1-MMP processing of αv integrin enhances breast cancer cell migration [32, 33], and MMP shedding of the ectodomain of P-cadherin facilitates breast cancer cell invasion [34]. MMPs can also promote breast tumor progression by targeting soluble molecules. Examples include protease activation cascades (activation of MMP-9 by MMP-3 [22], activation of MMP-2 by MT1-MMP [35]), the activation of latent TGF-β by MMP-2 and MMP-9 [23], and the N-terminal truncation of interleukin-8 (IL-8) by MMP-9, increasing its neutrophil-activating potential by an order of magnitude [36].
Transgenic or knockout mouse models have been used to establish specific effects of individual MMPs on mammary tumor development (reviewed in [37]). MMP-3 overexpression driven by the whey acidic protein (WAP) promoter, most active in mammary gland epithelial cells from mid-pregnancy and during lactation, led to widespread premalignant alterations and spontaneous tumor formation [38]. Similarly, overexpression of MMP-7 under control of the mouse mammary tumor virus (MMTV) promoter, which is active during puberty and greatly enhanced during pregnancy, resulted in spontaneous formation of premalignant mammary hyperplasias, and accelerated tumor formation in bitransgenic MMTV-MMP-7/neu mice [39]. MMTV-driven overexpression of MT1-MMP also led to premalignant mammary gland abnormalities and spontaneous adenocarcinoma [40]. In studies with MMP-11 knockout mice subjected to 7,12-dimethylbenzanthracene (DMBA)-induced carcinogenesis, MMP-11 null mice developed fewer tumors [41]; MMP-11 null mice also developed fewer spontaneous tumors in the mammary gland cancer prone MMTV-ras model [42]. One clear conclusion from these studies is that some MMPs can act as tumor promoters in mammary carcinogenesis, impacting neoplastic risk from the very earliest stages of premalignant change [38, 43].
MMPs can also modulate later stages of cancer progression in genetic models of breast cancer. For example, knockout of MMP-9 in the MMTV-polyoma virus middle T-antigen (PyMT or PyVT) multistage mammary tumorigenesis model resulted in an 80% reduction in lung metastatic burden, indicating the importance of MMP-9 in metastasis and angiogenesis in this model [44]. In another study employing the MMTV-PyMT tumorigenesis model, MT1-MMP null mammary glands transplanted into syngeneic mice developed tumors with a markedly reduced capacity to metastasize to the lungs, compared with an MT1-MMP sufficient control group, demonstrating a role for tumor MT1-MMP in the metastatic process [45]. In a study investigating the roles of MMPs in recruitment of stromal bone-resorbing osteoclasts to breast-to-bone metastases, mammary tumor cells implanted into the bones of MMP-7 null mice formed smaller, slower growing tumors with recruitment of fewer osteoclasts and less osteolysis, implicating MMP-7 in this aspect of metastatic progression [46].
Of course, MMPs do not act as universal tumor promoters under all circumstances, and the effects observed can also vary depending upon the model and upon the genetic background of the mice [43, 44]. In contrast with the protumorigenic effects of MMP-3 in the WAP promoter model [38], MMTV-driven MMP-3 expression in a different strain of mice did not lead to spontaneous tumorigenesis, and in a DMBA chemical carcinogenesis protocol, MMTV-MMP-e mice were reported to have fewer mammary gland tumors and more apoptotic cells [43, 47]. In contrast with the tumor promoting effect of MT1-MMP in mice with mammary-directed overexpression of this protease [40], MT1-MMP had a growth suppressing effect in the MMTV-PyMT genetically induced model when tumorigenesis in MT1-MMP null versus MT1-MMP sufficient mammary glands were compared [45]. For MMP-9 promotion of breast-to-lung metastasis as well, the genetic background of the mice was a determining factor, as C57BL/6 mice showed MMP-9 dependent promotion of metastatic growth, whereas no significant differences were observed between wt and MMP-9 null mice of the FVB/N background [44]. These observations underscore the complexity of the process of tumor development, in which MMPs must interact with many other variables; it has been suggested that as in mice, genetic modifiers present in human patient populations may distinguish subgroups likely to benefit from therapeutic intervention in MMP-mediated processes [44].

MMPs and Physiological EMT

EMT is a process integral to the formation of many tissues and organs during development [4851]. Activation of developmental EMT has been found to follow a defined sequence of events: morphogenesis of the epithelial tissue and specification of the cells that will undergo EMT, disruption or degradation of the basement membrane, breakdown of the epithelial tissue structure followed by ingression of the separated cells, and differentiation to the motile mesenchymal phenotype [49]. While MMPs have long been suspected to play roles in many different EMT-related tissue morphogenesis and cell migration processes, direct evidence of MMP involvement has been best characterized for neural crest delamination, endocardial cushion invasion, and mammary gland branching morphogenesis. EMT of the neural crest during embryogenesis releases mesenchymal cells that migrate through the body, giving rise to a wide variety of tissue types, including glial and neuronal cells, adrenal glandular tissues, melanocytes, and skeletal and connective tissues [49, 52] (Fig. 2a). MMP-2 becomes activated in the neural cells as they are undergoing EMT, but inactivated as the cells begin to disperse [5356]; blocking MMP-2 inhibits EMT without affecting the migration of the detached neural crest cells [53]. EMT of embryonic endocardial cells into the endocardial cushion creates precursors of the valvular and septal structures (Fig. 2b) [57], and also is dependent upon expression of MMP-2, as treatment with MMP inhibitors blocks mesenchyme formation [58, 59]. Studies using endocardial cushion explants grown on collagen gels revealed that MMP-2-dependent EMT involves degradation of collagen-IV [58], and requires specific association of MMP-2 with integrin αvβ3 [60].
Unlike many other tissues, the majority of mammary gland development occurs postnatally. During puberty, the rudimentary mammary gland grows into the fat pad through ductal extension and branching morphogenesis [6163]. Extension of the ducts into the fat pad occurs at the endbuds, invasive structures that express high levels of EMT-associated transcription factors, including Snail and Twist [64] as well as MMP-2 and MT1-MMP [65]. Mammary branching morphogenesis occurs by two distinct mechanisms: primary branching through endbud bifurcation, and secondary branching, a process strikingly similar to developmental EMT, in which differentiated, ductal epithelium dedifferentiates, detaches from the adjacent epithelial cells, penetrates the basement membrane, and invades into the surrounding tissue (Fig. 2c). MMP-3 is a key mediator of secondary branch formation, as transgenic mice lacking MMP-3 expression have significantly reduced secondary branching, while the WAP-MMP-3 mice have increased secondary branching and ductal complexity [65, 66]. Upregulation of MMP-3 has also been implicated in the increased side-branching observed in transgenic mice in which retinoic acid signaling pathways are inhibited [67]. The mechanism by which MMP-3 induces branching morphogenesis has been investigated in 3D culture models in which mouse mammary epithelial cell clusters are grown in collagen I gels. These studies have shown that epimorphin, a stromal cell-produced morphogen, induces expression of MMP-3, and that this is both necessary and sufficient for activation of the branching process [6871]. Activation of the fibroblast growth receptor signaling pathway, which has also been implicated in mammary branching morphogenesis, also induced MMP-3 expression and branch initiation in mammary epithelial cells grown in 3D collagen [72].

MMPs and EMT in Breast Cancer

MMPs have been associated with EMT in cancer progression through three distinct mechanisms: (a) elevated levels of MMPs in the tumor microenvironment can directly induce EMT in epithelial cells, (b) cancer cells that undergo EMT can produce more MMPs, facilitating cell invasion and metastasis, and (c) EMT can generate activated stromal-like cells that drive cancer progression via further MMP production. The most dramatic of these is MMP-dependent activation of the EMT program (Fig. 3a), seen in a variety of epithelial cell types, including kidney [7376], ovary [77], lens [78], lung [79], and prostate [80], although MMP-induced EMT has been best characterized in mammary epithelial cells. Tumors that developed in the WAP-MMP-3 mice showed mesenchymal characteristics [38, 81, 82], and dissection of this process revealed that exposure of cultured mouse mammary epithelial cells to MMP-3 directly activates EMT [31, 83]. MMP-3 mediates these effects by stimulating increased expression of Rac1b [84], a constitutively activated splice variant of Rac1 found in breast and colorectal cancer cells [8589], which in turn triggers EMT by increasing levels of cellular reactive oxygen species [84, 90]. While the process by which MMP-3 initiates these effects has not been completely defined, MMP-3 has been shown to cleave E-cadherin, promoting dissolution of epithelial cells and releasing a bioactive fragment of E-cadherin that induces cell motility [30, 31]. It is likely that many studies in which MMPs have been seen to stimulate cancer cell motility and invasion, although not directly investigating these phenomena in the context of EMT, have in fact been observing the cellular consequences of an incomplete activation of the EMT program. Unlike developmental EMT, where MMPs are a component of an organized morphogenic program, the chaotic and MMP-enriched tumor microenvironment induces an uncoordinated and incomplete EMT. As a consequence, these EMT-activated cells may acquire significant tumor-promoting abilities even as they retain many of their original characteristics, making it difficult to distinguish them from the original tumor mass from which they are derived.
Breast cancer cells which have undergone EMT also show increased expression of MMPs, facilitating their invasive, metastatic characteristics (Fig. 3b; as this topic was comprehensively reviewed in 2005 [91], only highlights and more recent studies will be covered here). Early investigations revealed that breast cancer cell lines expressing mesenchymal markers often expressed MMPs, and that suppression of these MMPs blocked their invasive and migratory characteristics [9294]. Subsequent investigations have identified MMP upregulation associated with a variety of EMT processes, although the specific MMPs induced seem to depend upon the nature of the EMT-inducing agent and the model system used. Transcriptional profiling studies of Ras-transformed mouse mammary epithelial cells induced to undergo EMT by treatment with TGFβ revealed MMP-2, MMP-12, and MMP-13 among the most upregulated transcripts [95, 96]. Culture of MCF10A cells at low density activated EMT-like changes associated with increased expression of MT1-MMP [97, 98], while induction of EMT in MCF10A cells by exposure to TGFβ or expression of ErbB2 stimulated expression of MMP-2 and MMP-9, respectively [99, 100]. Decreased expression of singleminded-2s in mouse mammary epithelial cells or in MCF-7 breast cancer cells activated EMT and expression of MMP-2 [101], while expression of Snail in MCF-7 cells induced an MT1-MMP and MT2-MMP-dependent invasion program [102]. Activation of EMT in NMuMg cells by treatment with hydrogen peroxide led to activation of MMP-3, MMP-10, and MMP-13 [103], while induction of EMT by the Abl tyrosine kinase in the same cell line led to MMP-3 and MMP-9 expression [104]. As breast cancer progression is a complex process, it may be unsurprising that distinct profiles of MMPs are activated in systems that model different breast cancer stages and disease subtypes.
EMT of cancer cells may produce stromal-like derivatives that, while not intrinsically malignant, act to facilitate tumor progression through production of MMPs (Fig. 3c). Myofibroblasts are principal components of the reactive stroma surrounding breast cancers, and these cells have been found to have powerful tumor-promoting characteristics [105108]. While myofibroblasts can be produced through activation of stromal fibroblasts or circulating fibrocytes, recent studies using mouse models have shown that myofibroblasts can be derived from epithelial cells by EMT [107, 109113]. EMT functions in human breast cancer as well: stromal-like and myofibroblast-like cells surrounding breast tumors have been found to be derived from the epithelial cancer cells [107, 114]. It is further known that mammographic density, an established risk factor for and potential precursor of breast cancer [115, 116], is associated with fibroblast accumulation [117122]. Studies of MMP localization in human tumors have shown that stromal fibroblasts are a major contributor to the production of many MMPs [123125], and tumor progression and poor prognosis is associated with stromal expression of MMP-1, MMP-7, and MMP-12 [126], and with fibroblast-specific production of MMP-9, MMP-11, and MT1-MMP [124, 125]. Further defining which MMPs are produced by breast cancer-associated myofibroblasts, and how these MMPs act in tumor progression, will provide insight into how EMT-driven tumor progression can best be targeted therapeutically.
Unfortunately, there have been very few studies that assess histological correlates of EMT with expression of MMPs in human breast tissues. Studies with metaplastic breast carcinoma, a relatively uncommon subtype for which ongoing EMT processes are evident, have found that stromelysin-3/MMP-11 expression in epithelial cells is a prognostic factor for disease progression—patients who expressed more MMP-11 in epithelial carcinoma cells had significantly shorter disease-free survival [127]. More recently, profiling studies of metaplastic breast carcinoma have found that altered expression of MMPs and TIMPS were found in patients with more rapid disease progression [128]. However, a direct connection between MMPs and EMT that can be assessed by histological characteristics awaits future research.

Therapeutic Targeting of MMP-promoted EMT

An obvious point for intervention in MMP-induced or mediated EMT is the catalytic inhibition of MMPs themselves. Unfortunately, clinical trials of first- and second-generation small molecule MMP-inhibiting drugs in breast cancer and other cancers proved disappointing [129]. A phase III trial of the MMP inhibitor marimastat in patients with metastatic breast cancer found no therapeutic benefit [130], while phase II trials of marimastat and rebimastat in patients with early-stage breast cancer concluded that large adjuvant trials with these agents were not feasible due to musculoskeletal toxicity and failure to achieve therapeutic plasma levels [131, 132]. Many of the problems with the MMP inhibitors tested to date appear to stem in large part from a lack of specificity; the drugs employed simply target too many enzymes. This is a critical problem, because some MMPs appear to protect against tumor progression at certain stages of breast cancer development, and inhibition of these MMPs at the wrong time can lead to increased tumor aggressiveness [27, 133135]. For example, high levels of MMP-8 have been shown to suppress breast cancer metastasis [136], potentially by increasing tumor cell adhesion to ECM and diminishing cellular invasive potential [137]; significantly, ribozyme-mediated knockdown of MMP-8 in a nonmetastatic, high MMP-8 breast cancer cell line conferred metastatic competence [136]. Thus, pharmacological inhibition of MMP-8 along with invasion- and metastasis-promoting MMPs would be anticipated to reduce or limit the potential benefit of the therapy.
As another consequence of poor specificity, clinical trials of MMP inhibitors were plagued by the serious side effect of musculoskeletal syndrome (MSS). This dose-limiting toxicity frequently resulted in failure to achieve targeted plasma levels, and in patients withdrawing from treatment, further compromising the statistical significance of trial outcomes [138]. The specific molecular target responsible for these side effects has not been conclusively identified; early candidates included MMP-1 and the ADAM family of metalloproteases, but synthetic inhibitors developed to minimize inhibition of these targets still produced MSS symptoms [138]. Remaining candidate mediators of MSS include MT1-MMP [135], metalloproteases outside of the MMP and ADAM families [139], or nonprotease metalloproteins [138]. To minimize off-target effects, well-tolerated MMP-directed therapeutics will need to achieve selectivity for the MMP family in preference to other metalloenzymes, as well as the ability to distinguish among MMPs.
The key challenges yet to be surmounted to bring MMP inhibitors to the clinic as an approach to combat MMP-mediated EMT and resulting cancer progression are (1) identification of the individual MMP targets implicated as primary drivers of EMT-promoted malignancy at specific points in tumor progression, and (2) development of therapeutic molecules capable of targeting these cancer-driving MMPs with exquisite selectivity. An attempt has already been made to synthesize existing data from current models into a master list of MMP drug targets versus “anti-targets”, for which pharmacological intervention would be presumed counterproductive [135]. However, the data currently available are insufficient to support definitive classification of most MMPs, particularly as questions remain regarding the extent to which various animal cancer models fully and faithfully reproduce the functional diversity of individual MMPs in cancer progression in humans. In particular, MMP-3, MMP-9, and MT1-MMP have all been suggested as drug anti-targets due to reports of antitumor effects associated with these MMPs in some model systems [135]; yet, the bulk of the literature supports the view that these are among the MMPs most directly implicated in promoting EMT, motility, invasion, and metastasis in cancer models. Rather than eliminating these MMPs from the drug target lineup, it would instead be prudent to cautiously pursue them, keeping in mind that further basic research into their functions in tumor development is necessary, and that their effective targeting for therapeutic benefit will require careful definition of the patient populations most likely to benefit, with regard to disease stage, pathological characteristics, and potential genetic modifiers. As an example of stage-specific considerations of potential importance in targeting MMP-induced EMT, it has been observed that MMP-3-induced EMT of breast epithelial cells is initially reversible upon withdrawal of the MMP, but eventually becomes permanent [31, 38], suggesting that therapeutic intervention with MMP inhibitors may be most effective at early stages of breast cancer development.
In the arena of more highly selective small molecule MMP inhibitors, slow progress is being made. These synthetic compounds typically feature a zinc-chelating group such as hydroxamate derivitized with peptidic or nonpeptidic groups designed to mimic a peptide substrate; they target the MMP active site zinc and substrate binding site [4, 140, 141]. Structure-based design of selective inhibitors has been hampered by the close structural homology of active sites and overlapping substrate specificities among the MMPs, and by the elastic and flexible nature of the MMP active site, which further complicates computational drug design even when high resolution crystal structures are available [141144]. Current approaches to small molecule MMP inhibitors include optimization of compounds based on an array of different zinc-binding groups to yield more selective inhibitors toward a variety of MMPs [4, 145], as well as the development of non-zinc-binding inhibitors that selectively target unique aspects of the MMP-13 active site [145]. A less conventional approach has pursued development of irreversible mechanism-based inhibitors, selective for gelatinases MMP-2 and MMP-9, that covalently modify the catalytic glutamate residue of the MMP active site [145, 146]. In yet another approach, several groups have attempted to exploit the selective substrate binding exosites present on MMP accessory domains to develop selective allosteric inhibitors of MMPs; while a promising concept, this approach has yet to yield highly potent and selective drug leads [7].
An alternative to small molecule MMP inhibitors is presented by macromolecular protein therapeutics. Promising candidates for development include engineered variants of the natural MMP-inhibiting TIMPs, and MMP-targeting therapeutic antibodies. TIMPs offer the advantage of an extensive contact surface ideally evolved for high affinity interaction with MMP targets. Although the four native TIMPs possess only a limited ability to differentiate between the many members of the MMP family, mutational studies have established the potential for modulating binding specificity by alteration of key residues at the MMP-TIMP interface [147152]. A recombinant triple mutant variant of the TIMP-1N-terminal domain, optimized for selectivity to MT1-MMP, was recently found to potently block MT1-MMP collagenase activity and CD44 shedding in breast cancer and fibrosarcoma cell culture models [153]. In another approach to selective MMP inhibition, several function blocking antibodies have been reported that selectively target individual MMPs [7]. In one recent and promising example, phage display technology was used to identify an MT1-MMP-selective human monoclonal antibody that blocked the proteolytic activity of the enzyme; this protein therapeutic was found to slow tumor progression and metastasis in an orthotopic xenograft model of breast cancer [154].
Thus, the challenges are clear: while some MMPs facilitate breast cancer development and could potentially be targeted for therapeutic benefit, others are essential for basic physiological processes, interference with which can have serious negative consequences. We need methods to target specific MMPs, as well as a much better understanding of which MMPs to target and when. Furthermore, while much has been learned about how to target the catalytic activities of MMPs, recent research has revealed that their noncatalytic accessory functions must also be considered. The efforts of chemists, biologists, bioengineers, and physicians must now be combined to discover selective drugs and reagents, to create the most informative experimental models in which to dissect the roles of MMPs in EMT-driven breast cancer progression, to develop and test optimal intervention strategies, and to effect the translation of these therapies into the clinic.

Financial Support

This work is supported by grants from the National Cancer Institute (CA122086, CA128660, and CA132879 to DCR), from the James and Esther King Foundation (07KN09 to DCR; 08KN12 to ESR), from the Bankhead-Coley Foundation (09BB17 to ESR), from the Susan B. Komen foundation (FAS0703855 to DCR), and by the Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE) grant CA116201 (PI James Ingle MD) from the National Institutes of Health.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://​creativecommons.​org/​licenses/​by-nc/​2.​0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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Literatur
1.
Zurück zum Zitat Quesada V, Ordonez GR, Sanchez LM, et al. The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res. 2009;37(Database issue):D239–43.PubMed Quesada V, Ordonez GR, Sanchez LM, et al. The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res. 2009;37(Database issue):D239–43.PubMed
2.
Zurück zum Zitat Tallant C, Marrero A, Gomis-Ruth FX. Matrix metalloproteinases: fold and function of their catalytic domains. Biochim Biophys Acta. 2009. Tallant C, Marrero A, Gomis-Ruth FX. Matrix metalloproteinases: fold and function of their catalytic domains. Biochim Biophys Acta. 2009.
3.
Zurück zum Zitat Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73.PubMed Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73.PubMed
4.
Zurück zum Zitat Overall CM, Kleifeld O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer. 2006;94(7):941–6.PubMed Overall CM, Kleifeld O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer. 2006;94(7):941–6.PubMed
5.
Zurück zum Zitat Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–39.PubMed Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–39.PubMed
6.
Zurück zum Zitat Rosenblum G, Meroueh S, Toth M, et al. Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen: challenging the cysteine switch dogma. J Am Chem Soc. 2007;129(44):13566–74.PubMed Rosenblum G, Meroueh S, Toth M, et al. Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen: challenging the cysteine switch dogma. J Am Chem Soc. 2007;129(44):13566–74.PubMed
7.
Zurück zum Zitat Sela-Passwell N, Rosenblum G, Shoham T, et al. Structural and functional bases for allosteric control of MMP activities: Can it pave the path for selective inhibition? Biochim Biophys Acta. 2009. Sela-Passwell N, Rosenblum G, Shoham T, et al. Structural and functional bases for allosteric control of MMP activities: Can it pave the path for selective inhibition? Biochim Biophys Acta. 2009.
8.
Zurück zum Zitat Allan JA, Docherty AJ, Barker PJ, et al. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J. 1995;309(Pt 1):299–306.PubMed Allan JA, Docherty AJ, Barker PJ, et al. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J. 1995;309(Pt 1):299–306.PubMed
9.
Zurück zum Zitat Bertini I, Fragai M, Luchinat C. Intra- and interdomain flexibility in matrix metalloproteinases: functional aspects and drug design. Curr Pharm Des. 2009;15(31):3592–605.PubMed Bertini I, Fragai M, Luchinat C. Intra- and interdomain flexibility in matrix metalloproteinases: functional aspects and drug design. Curr Pharm Des. 2009;15(31):3592–605.PubMed
10.
Zurück zum Zitat Piccard H, Van den Steen PE, Opdenakker G. Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins. J Leukoc Biol. 2007;81(4):870–92.PubMed Piccard H, Van den Steen PE, Opdenakker G. Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins. J Leukoc Biol. 2007;81(4):870–92.PubMed
11.
Zurück zum Zitat Chung L, Dinakarpandian D, Yoshida N, et al. Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. EMBO J. 2004;23(15):3020–30.PubMed Chung L, Dinakarpandian D, Yoshida N, et al. Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. EMBO J. 2004;23(15):3020–30.PubMed
12.
Zurück zum Zitat Lauer-Fields JL, Chalmers MJ, Busby SA, et al. Identification of specific hemopexin-like domain residues that facilitate matrix metalloproteinase collagenolytic activity. J Biol Chem. 2009;284(36):24017–24.PubMed Lauer-Fields JL, Chalmers MJ, Busby SA, et al. Identification of specific hemopexin-like domain residues that facilitate matrix metalloproteinase collagenolytic activity. J Biol Chem. 2009;284(36):24017–24.PubMed
13.
Zurück zum Zitat Gioia M, Monaco S, Fasciglione GF, et al. Characterization of the mechanisms by which gelatinase A, neutrophil collagenase, and membrane-type metalloproteinase MMP-14 recognize collagen I and enzymatically process the two alpha-chains. J Mol Biol. 2007;368(4):1101–13.PubMed Gioia M, Monaco S, Fasciglione GF, et al. Characterization of the mechanisms by which gelatinase A, neutrophil collagenase, and membrane-type metalloproteinase MMP-14 recognize collagen I and enzymatically process the two alpha-chains. J Mol Biol. 2007;368(4):1101–13.PubMed
14.
Zurück zum Zitat Tam EM, Moore TR, Butler GS, et al. Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. J Biol Chem. 2004;279(41):43336–44.PubMed Tam EM, Moore TR, Butler GS, et al. Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. J Biol Chem. 2004;279(41):43336–44.PubMed
15.
Zurück zum Zitat Roeb E, Schleinkofer K, Kernebeck T, et al. The matrix metalloproteinase 9 (mmp-9) hemopexin domain is a novel gelatin binding domain and acts as an antagonist. J Biol Chem. 2002;277(52):50326–32.PubMed Roeb E, Schleinkofer K, Kernebeck T, et al. The matrix metalloproteinase 9 (mmp-9) hemopexin domain is a novel gelatin binding domain and acts as an antagonist. J Biol Chem. 2002;277(52):50326–32.PubMed
16.
Zurück zum Zitat Monaco S, Gioia M, Rodriguez J, et al. Modulation of the proteolytic activity of matrix metalloproteinase-2 (gelatinase A) on fibrinogen. Biochem J. 2007;402(3):503–13.PubMed Monaco S, Gioia M, Rodriguez J, et al. Modulation of the proteolytic activity of matrix metalloproteinase-2 (gelatinase A) on fibrinogen. Biochem J. 2007;402(3):503–13.PubMed
17.
Zurück zum Zitat McQuibban GA, Gong JH, Tam EM, et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science. 2000;289(5482):1202–6.PubMed McQuibban GA, Gong JH, Tam EM, et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science. 2000;289(5482):1202–6.PubMed
18.
Zurück zum Zitat McQuibban GA, Butler GS, Gong JH, et al. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem. 2001;276(47):43503–8.PubMed McQuibban GA, Butler GS, Gong JH, et al. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem. 2001;276(47):43503–8.PubMed
19.
Zurück zum Zitat Overall CM, McQuibban GA, Clark-Lewis I. Discovery of chemokine substrates for matrix metalloproteinases by exosite scanning: a new tool for degradomics. Biol Chem. 2002;383(7–8):1059–66.PubMed Overall CM, McQuibban GA, Clark-Lewis I. Discovery of chemokine substrates for matrix metalloproteinases by exosite scanning: a new tool for degradomics. Biol Chem. 2002;383(7–8):1059–66.PubMed
20.
Zurück zum Zitat Ogata Y, Itoh Y, Nagase H. Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases. J Biol Chem. 1995;270(31):18506–11.PubMed Ogata Y, Itoh Y, Nagase H. Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases. J Biol Chem. 1995;270(31):18506–11.PubMed
21.
Zurück zum Zitat Goldberg GI, Strongin A, Collier IE, et al. Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem. 1992;267(7):4583–91.PubMed Goldberg GI, Strongin A, Collier IE, et al. Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem. 1992;267(7):4583–91.PubMed
22.
Zurück zum Zitat Ramos-DeSimone N, Hahn-Dantona E, Sipley J, et al. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem. 1999;274(19):13066–76.PubMed Ramos-DeSimone N, Hahn-Dantona E, Sipley J, et al. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem. 1999;274(19):13066–76.PubMed
23.
Zurück zum Zitat Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.PubMed Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.PubMed
24.
Zurück zum Zitat Mori H, Tomari T, Koshikawa N, et al. CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J. 2002;21(15):3949–59.PubMed Mori H, Tomari T, Koshikawa N, et al. CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J. 2002;21(15):3949–59.PubMed
25.
Zurück zum Zitat Kajita M, Itoh Y, Chiba T, et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001;153(5):893–904.PubMed Kajita M, Itoh Y, Chiba T, et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001;153(5):893–904.PubMed
26.
Zurück zum Zitat Mori H, Gjorevski N, Inman JL, et al. Self-organization of engineered epithelial tubules by differential cellular motility. Proc Natl Acad Sci U S A. 2009;106(35):14890–5.PubMed Mori H, Gjorevski N, Inman JL, et al. Self-organization of engineered epithelial tubules by differential cellular motility. Proc Natl Acad Sci U S A. 2009;106(35):14890–5.PubMed
27.
Zurück zum Zitat Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.PubMed Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.PubMed
28.
Zurück zum Zitat Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221–33.PubMed Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221–33.PubMed
29.
Zurück zum Zitat Boire A, Covic L, Agarwal A, et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005;120(3):303–13.PubMed Boire A, Covic L, Agarwal A, et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005;120(3):303–13.PubMed
30.
Zurück zum Zitat Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci. 2001;114(Pt 1):111–8.PubMed Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci. 2001;114(Pt 1):111–8.PubMed
31.
Zurück zum Zitat Lochter A, Galosy S, Muschler J, et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997;139(7):1861–72.PubMed Lochter A, Galosy S, Muschler J, et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997;139(7):1861–72.PubMed
32.
Zurück zum Zitat Deryugina EI, Ratnikov BI, Postnova TI, et al. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem. 2002;277(12):9749–56.PubMed Deryugina EI, Ratnikov BI, Postnova TI, et al. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem. 2002;277(12):9749–56.PubMed
33.
Zurück zum Zitat Ratnikov BI, Rozanov DV, Postnova TI, et al. An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase. J Biol Chem. 2002;277(9):7377–85.PubMed Ratnikov BI, Rozanov DV, Postnova TI, et al. An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase. J Biol Chem. 2002;277(9):7377–85.PubMed
34.
Zurück zum Zitat Ribeiro AS, Albergaria A, Sousa B, et al. Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells. Oncogene. 2010;29(3):392–402.PubMed Ribeiro AS, Albergaria A, Sousa B, et al. Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells. Oncogene. 2010;29(3):392–402.PubMed
35.
Zurück zum Zitat Strongin AY, Collier I, Bannikov G, et al. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995;270(10):5331–8.PubMed Strongin AY, Collier I, Bannikov G, et al. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995;270(10):5331–8.PubMed
36.
Zurück zum Zitat Van den Steen PE, Proost P, Wuyts A, et al. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood. 2000;96(8):2673–81.PubMed Van den Steen PE, Proost P, Wuyts A, et al. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood. 2000;96(8):2673–81.PubMed
37.
Zurück zum Zitat Almholt K, Green KA, Juncker-Jensen A, et al. Extracellular proteolysis in transgenic mouse models of breast cancer. J Mammary Gland Biol Neoplasia. 2007;12(1):83–97.PubMed Almholt K, Green KA, Juncker-Jensen A, et al. Extracellular proteolysis in transgenic mouse models of breast cancer. J Mammary Gland Biol Neoplasia. 2007;12(1):83–97.PubMed
38.
Zurück zum Zitat Sternlicht MD, Lochter A, Sympson CJ, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 1999;98(2):137–46.PubMed Sternlicht MD, Lochter A, Sympson CJ, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 1999;98(2):137–46.PubMed
39.
Zurück zum Zitat Rudolph-Owen LA, Chan R, Muller WJ, et al. The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res. 1998;58(23):5500–6.PubMed Rudolph-Owen LA, Chan R, Muller WJ, et al. The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res. 1998;58(23):5500–6.PubMed
40.
Zurück zum Zitat Ha HY, Moon HB, Nam MS, et al. Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice. Cancer Res. 2001;61(3):984–90.PubMed Ha HY, Moon HB, Nam MS, et al. Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice. Cancer Res. 2001;61(3):984–90.PubMed
41.
Zurück zum Zitat Masson R, Lefebvre O, Noel A, et al. In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol. 1998;140(6):1535–41.PubMed Masson R, Lefebvre O, Noel A, et al. In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol. 1998;140(6):1535–41.PubMed
42.
Zurück zum Zitat Andarawewa KL, Boulay A, Masson R, et al. Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. Cancer Res. 2003;63(18):5844–9.PubMed Andarawewa KL, Boulay A, Masson R, et al. Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. Cancer Res. 2003;63(18):5844–9.PubMed
43.
Zurück zum Zitat Matrisian LM. Cancer biology: extracellular proteinases in malignancy. Curr Biol. 1999;9(20):R776–8.PubMed Matrisian LM. Cancer biology: extracellular proteinases in malignancy. Curr Biol. 1999;9(20):R776–8.PubMed
44.
Zurück zum Zitat Martin MD, Carter KJ, Jean-Philippe SR, et al. Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background. Cancer Res. 2008;68(15):6251–9.PubMed Martin MD, Carter KJ, Jean-Philippe SR, et al. Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background. Cancer Res. 2008;68(15):6251–9.PubMed
45.
Zurück zum Zitat Szabova L, Chrysovergis K, Yamada SS, et al. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene. 2008;27(23):3274–81.PubMed Szabova L, Chrysovergis K, Yamada SS, et al. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene. 2008;27(23):3274–81.PubMed
46.
Zurück zum Zitat Thiolloy S, Halpern J, Holt GE, et al. Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis. Cancer Res. 2009;69(16):6747–55.PubMed Thiolloy S, Halpern J, Holt GE, et al. Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis. Cancer Res. 2009;69(16):6747–55.PubMed
47.
Zurück zum Zitat Witty JP, Lempka T, Coffey Jr RJ, et al. Decreased tumor formation in 7, 12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res. 1995;55(7):1401–6.PubMed Witty JP, Lempka T, Coffey Jr RJ, et al. Decreased tumor formation in 7, 12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res. 1995;55(7):1401–6.PubMed
48.
Zurück zum Zitat Radisky DC. Epithelial-mesenchymal transition. J Cell Sci. 2005;118(Pt 19):4325–6.PubMed Radisky DC. Epithelial-mesenchymal transition. J Cell Sci. 2005;118(Pt 19):4325–6.PubMed
49.
Zurück zum Zitat Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.PubMed Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.PubMed
50.
Zurück zum Zitat Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMed Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMed
51.
Zurück zum Zitat Hugo H, Ackland ML, Blick T, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.PubMed Hugo H, Ackland ML, Blick T, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.PubMed
52.
Zurück zum Zitat Duband JL. Neural crest delamination and migration: integrating regulations of cell interactions, locomotion, survival and fate. Adv Exp Med Biol. 2006;589:45–77.PubMed Duband JL. Neural crest delamination and migration: integrating regulations of cell interactions, locomotion, survival and fate. Adv Exp Med Biol. 2006;589:45–77.PubMed
53.
Zurück zum Zitat Duong TD, Erickson CA. MMP-2 plays an essential role in producing epithelial-mesenchymal transformations in the avian embryo. Dev Dyn. 2004;229(1):42–53.PubMed Duong TD, Erickson CA. MMP-2 plays an essential role in producing epithelial-mesenchymal transformations in the avian embryo. Dev Dyn. 2004;229(1):42–53.PubMed
54.
Zurück zum Zitat Cai DH, Brauer PR. Synthetic matrix metalloproteinase inhibitor decreases early cardiac neural crest migration in chicken embryos. Dev Dyn. 2002;224(4):441–9.PubMed Cai DH, Brauer PR. Synthetic matrix metalloproteinase inhibitor decreases early cardiac neural crest migration in chicken embryos. Dev Dyn. 2002;224(4):441–9.PubMed
55.
Zurück zum Zitat Cai DH, Vollberg Sr TM, Hahn-Dantona E, et al. MMP-2 expression during early avian cardiac and neural crest morphogenesis. Anat Rec. 2000;259(2):168–79.PubMed Cai DH, Vollberg Sr TM, Hahn-Dantona E, et al. MMP-2 expression during early avian cardiac and neural crest morphogenesis. Anat Rec. 2000;259(2):168–79.PubMed
56.
Zurück zum Zitat Cantemir V, Cai DH, Reedy MV, et al. Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression during cardiac neural crest cell migration and its role in proMMP-2 activation. Dev Dyn. 2004;231(4):709–19.PubMed Cantemir V, Cai DH, Reedy MV, et al. Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression during cardiac neural crest cell migration and its role in proMMP-2 activation. Dev Dyn. 2004;231(4):709–19.PubMed
57.
Zurück zum Zitat Runyan RB, Heimark RL, Camenisch TD, et al. Epithelial-Mesenchymal Transformation in the Embryonic Heart. In: Savagner P, editors. Rise and Fall of Epithelial Phenotype: Springer US; 2005. p. 40–55. Runyan RB, Heimark RL, Camenisch TD, et al. Epithelial-Mesenchymal Transformation in the Embryonic Heart. In: Savagner P, editors. Rise and Fall of Epithelial Phenotype: Springer US; 2005. p. 40–55.
58.
Zurück zum Zitat Song W, Jackson K, McGuire PG. Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. Dev Biol. 2000;227(2):606–17.PubMed Song W, Jackson K, McGuire PG. Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. Dev Biol. 2000;227(2):606–17.PubMed
59.
Zurück zum Zitat Alexander SM, Jackson KJ, Bushnell KM, et al. Spatial and temporal expression of the 72-kDa type IV collagenase (MMP-2) correlates with development and differentiation of valves in the embryonic avian heart. Dev Dyn. 1997;209(3):261–8.PubMed Alexander SM, Jackson KJ, Bushnell KM, et al. Spatial and temporal expression of the 72-kDa type IV collagenase (MMP-2) correlates with development and differentiation of valves in the embryonic avian heart. Dev Dyn. 1997;209(3):261–8.PubMed
60.
Zurück zum Zitat Rupp PA, Visconti RP, Czirok A, et al. Matrix metalloproteinase 2-integrin alpha(v)beta3 binding is required for mesenchymal cell invasive activity but not epithelial locomotion: a computational time-lapse study. Mol Biol Cell. 2008;19(12):5529–40.PubMed Rupp PA, Visconti RP, Czirok A, et al. Matrix metalloproteinase 2-integrin alpha(v)beta3 binding is required for mesenchymal cell invasive activity but not epithelial locomotion: a computational time-lapse study. Mol Biol Cell. 2008;19(12):5529–40.PubMed
61.
Zurück zum Zitat Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004;6(1):1–11.PubMed Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004;6(1):1–11.PubMed
62.
Zurück zum Zitat Sternlicht MD, Kouros-Mehr H, Lu P, et al. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006;74(7):365–81.PubMed Sternlicht MD, Kouros-Mehr H, Lu P, et al. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006;74(7):365–81.PubMed
63.
Zurück zum Zitat Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296(5570):1046–9.PubMed Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296(5570):1046–9.PubMed
64.
Zurück zum Zitat Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235(12):3404–12.PubMed Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235(12):3404–12.PubMed
65.
Zurück zum Zitat Wiseman BS, Sternlicht MD, Lund LR, et al. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J Cell Biol. 2003;162(6):1123–33.PubMed Wiseman BS, Sternlicht MD, Lund LR, et al. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J Cell Biol. 2003;162(6):1123–33.PubMed
66.
Zurück zum Zitat Sympson CJ, Talhouk RS, Alexander CM, et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol. 1994;125(3):681–93.PubMed Sympson CJ, Talhouk RS, Alexander CM, et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol. 1994;125(3):681–93.PubMed
67.
Zurück zum Zitat Wang YA, Shen K, Wang Y, et al. Retinoic acid signaling is required for proper morphogenesis of mammary gland. Dev Dyn. 2005;234(4):892–9.PubMed Wang YA, Shen K, Wang Y, et al. Retinoic acid signaling is required for proper morphogenesis of mammary gland. Dev Dyn. 2005;234(4):892–9.PubMed
68.
Zurück zum Zitat Hirai Y, Lochter A, Galosy S, et al. Epimorphin functions as a key morphoregulator for mammary epithelial cells. J Cell Biol. 1998;140(1):159–69.PubMed Hirai Y, Lochter A, Galosy S, et al. Epimorphin functions as a key morphoregulator for mammary epithelial cells. J Cell Biol. 1998;140(1):159–69.PubMed
69.
Zurück zum Zitat Hirai Y, Radisky D, Boudreau R, et al. Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta. J Cell Biol. 2001;153(4):785–94.PubMed Hirai Y, Radisky D, Boudreau R, et al. Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta. J Cell Biol. 2001;153(4):785–94.PubMed
70.
Zurück zum Zitat Radisky DC, Hirai Y, Bissell MJ. Delivering the message: epimorphin and mammary epithelial morphogenesis. Trends Cell Biol. 2003;13(8):426–34.PubMed Radisky DC, Hirai Y, Bissell MJ. Delivering the message: epimorphin and mammary epithelial morphogenesis. Trends Cell Biol. 2003;13(8):426–34.PubMed
71.
Zurück zum Zitat Chen CS, Nelson CM, Khauv D, et al. Homology with vesicle fusion mediator syntaxin-1a predicts determinants of epimorphin/syntaxin-2 function in mammary epithelial morphogenesis. J Biol Chem. 2009;284(11):6877–84.PubMed Chen CS, Nelson CM, Khauv D, et al. Homology with vesicle fusion mediator syntaxin-1a predicts determinants of epimorphin/syntaxin-2 function in mammary epithelial morphogenesis. J Biol Chem. 2009;284(11):6877–84.PubMed
72.
Zurück zum Zitat Xian W, Schwertfeger KL, Vargo-Gogola T, et al. Pleiotropic effects of FGFR1 on cell proliferation, survival, and migration in a 3D mammary epithelial cell model. J Cell Biol. 2005;171(4):663–73.PubMed Xian W, Schwertfeger KL, Vargo-Gogola T, et al. Pleiotropic effects of FGFR1 on cell proliferation, survival, and migration in a 3D mammary epithelial cell model. J Cell Biol. 2005;171(4):663–73.PubMed
73.
Zurück zum Zitat Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003;162(6):1937–49.PubMed Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003;162(6):1937–49.PubMed
74.
Zurück zum Zitat Cheng S, Pollock AS, Mahimkar R, et al. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J. 2006;20(11):1898–900.PubMed Cheng S, Pollock AS, Mahimkar R, et al. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J. 2006;20(11):1898–900.PubMed
75.
Zurück zum Zitat Tan TK, Zheng G, Hsu TT, et al. Macrophage Matrix Metalloproteinase-9 Mediates Epithelial-Mesenchymal Transition in Vitro in Murine Renal Tubular Cells. Am J Pathol. 2010. Tan TK, Zheng G, Hsu TT, et al. Macrophage Matrix Metalloproteinase-9 Mediates Epithelial-Mesenchymal Transition in Vitro in Murine Renal Tubular Cells. Am J Pathol. 2010.
76.
Zurück zum Zitat Zheng G, Lyons JG, Tan TK, et al. Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells. Am J Pathol. 2009;175(2):580–91.PubMed Zheng G, Lyons JG, Tan TK, et al. Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells. Am J Pathol. 2009;175(2):580–91.PubMed
77.
Zurück zum Zitat Cowden Dahl KD, Symowicz J, Ning Y, et al. Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res. 2008;68(12):4606–13.PubMed Cowden Dahl KD, Symowicz J, Ning Y, et al. Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res. 2008;68(12):4606–13.PubMed
78.
Zurück zum Zitat West-Mays JA, Pino G. Matrix metalloproteinases as mediators of primary and secondary cataracts. Expert Rev Ophthalmol. 2007;2(6):931–8.PubMed West-Mays JA, Pino G. Matrix metalloproteinases as mediators of primary and secondary cataracts. Expert Rev Ophthalmol. 2007;2(6):931–8.PubMed
79.
Zurück zum Zitat Illman SA, Lehti K, Keski-Oja J, et al. Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci. 2006;119(Pt 18):3856–65.PubMed Illman SA, Lehti K, Keski-Oja J, et al. Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci. 2006;119(Pt 18):3856–65.PubMed
80.
Zurück zum Zitat Cao J, Chiarelli C, Richman O, et al. Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. J Biol Chem. 2008;283(10):6232–40.PubMed Cao J, Chiarelli C, Richman O, et al. Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. J Biol Chem. 2008;283(10):6232–40.PubMed
81.
Zurück zum Zitat Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene. 2000;19:1102–13.PubMed Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene. 2000;19:1102–13.PubMed
82.
Zurück zum Zitat Sympson CJ, Bissell MJ, Werb Z. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol. 1995;6(3):159–63.PubMed Sympson CJ, Bissell MJ, Werb Z. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol. 1995;6(3):159–63.PubMed
83.
Zurück zum Zitat Lochter A, Srebrow A, Sympson CJ, et al. Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem. 1997;272(8):5007–15.PubMed Lochter A, Srebrow A, Sympson CJ, et al. Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem. 1997;272(8):5007–15.PubMed
84.
Zurück zum Zitat Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436(7047):123–7.PubMed Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436(7047):123–7.PubMed
85.
Zurück zum Zitat Fiegen D, Haeusler LC, Blumenstein L, et al. Alternative splicing of Rac1 generates Rac1b, a self-activating GTPase. J Biol Chem. 2004;279(6):4743–9.PubMed Fiegen D, Haeusler LC, Blumenstein L, et al. Alternative splicing of Rac1 generates Rac1b, a self-activating GTPase. J Biol Chem. 2004;279(6):4743–9.PubMed
86.
Zurück zum Zitat Matos P, Collard JG, Jordan P. Tumor-related alternatively spliced Rac1b is not regulated by Rho-GDP dissociation inhibitors and exhibits selective downstream signaling. J Biol Chem. 2003;278(50):50442–8.PubMed Matos P, Collard JG, Jordan P. Tumor-related alternatively spliced Rac1b is not regulated by Rho-GDP dissociation inhibitors and exhibits selective downstream signaling. J Biol Chem. 2003;278(50):50442–8.PubMed
87.
Zurück zum Zitat Singh A, Karnoub AE, Palmby TR, et al. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene. 2004;23(58):9369–80.PubMed Singh A, Karnoub AE, Palmby TR, et al. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene. 2004;23(58):9369–80.PubMed
88.
Zurück zum Zitat Jordan P, Brazao R, Boavida MG, et al. Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene. 1999;18(48):6835–9.PubMed Jordan P, Brazao R, Boavida MG, et al. Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene. 1999;18(48):6835–9.PubMed
89.
Zurück zum Zitat Schnelzer A, Prechtel D, Knaus U, et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene. 2000;19(26):3013–20.PubMed Schnelzer A, Prechtel D, Knaus U, et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene. 2000;19(26):3013–20.PubMed
90.
Zurück zum Zitat Nelson CM, Khauv D, Bissell MJ, et al. Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem. 2008. Nelson CM, Khauv D, Bissell MJ, et al. Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem. 2008.
91.
Zurück zum Zitat Gilles C, Newgreen DF, Sato H, et al. Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition: Implications for Carcinoma Metastasis. In: Savagner P, editor. Rise and Fall of Epithelial Phenotype: Springer US; 2005. p. 297–315. Gilles C, Newgreen DF, Sato H, et al. Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition: Implications for Carcinoma Metastasis. In: Savagner P, editor. Rise and Fall of Epithelial Phenotype: Springer US; 2005. p. 297–315.
92.
Zurück zum Zitat Gilles C, Polette M, Seiki M, et al. Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest. 1997;76(5):651–60.PubMed Gilles C, Polette M, Seiki M, et al. Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest. 1997;76(5):651–60.PubMed
93.
Zurück zum Zitat Gilles C, Polette M, Birembaut P, et al. Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. Clin Exp Metastasis. 1997;15(5):519–26.PubMed Gilles C, Polette M, Birembaut P, et al. Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. Clin Exp Metastasis. 1997;15(5):519–26.PubMed
94.
Zurück zum Zitat Martorana AM, Zheng G, Crowe TC, et al. Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. Cancer Res. 1998;58(21):4970–9.PubMed Martorana AM, Zheng G, Crowe TC, et al. Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. Cancer Res. 1998;58(21):4970–9.PubMed
95.
Zurück zum Zitat Janda E, Lehmann K, Killisch I, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol. 2002;156(2):299–313.PubMed Janda E, Lehmann K, Killisch I, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol. 2002;156(2):299–313.PubMed
96.
Zurück zum Zitat Jechlinger M, Grunert S, Tamir IH, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene. 2003;22(46):7155–69.PubMed Jechlinger M, Grunert S, Tamir IH, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene. 2003;22(46):7155–69.PubMed
97.
Zurück zum Zitat Gilles C, Polette M, Coraux C, et al. Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration. J Cell Sci. 2001;114(Pt 16):2967–76.PubMed Gilles C, Polette M, Coraux C, et al. Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration. J Cell Sci. 2001;114(Pt 16):2967–76.PubMed
98.
Zurück zum Zitat Sarrio D, Rodriguez-Pinilla SM, Hardisson D, et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989–97.PubMed Sarrio D, Rodriguez-Pinilla SM, Hardisson D, et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989–97.PubMed
99.
Zurück zum Zitat Kim ES, Sohn YW, Moon A. TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett. 2007;252(1):147–56.PubMed Kim ES, Sohn YW, Moon A. TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett. 2007;252(1):147–56.PubMed
100.
Zurück zum Zitat Kim IY, Yong HY, Kang KW, et al. Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. Cancer Lett. 2009;275(2):227–33.PubMed Kim IY, Yong HY, Kang KW, et al. Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. Cancer Lett. 2009;275(2):227–33.PubMed
101.
Zurück zum Zitat Laffin B, Wellberg E, Kwak HI, et al. Loss of singleminded-2s in the mouse mammary gland induces an epithelial-mesenchymal transition associated with up-regulation of slug and matrix metalloprotease 2. Mol Cell Biol. 2008;28(6):1936–46.PubMed Laffin B, Wellberg E, Kwak HI, et al. Loss of singleminded-2s in the mouse mammary gland induces an epithelial-mesenchymal transition associated with up-regulation of slug and matrix metalloprotease 2. Mol Cell Biol. 2008;28(6):1936–46.PubMed
102.
Zurück zum Zitat Ota I, Li XY, Hu Y, et al. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A. 2009;106(48):20318–23.PubMed Ota I, Li XY, Hu Y, et al. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A. 2009;106(48):20318–23.PubMed
103.
Zurück zum Zitat Mori K, Shibanuma M, Nose K. Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res. 2004;64(20):7464–72.PubMed Mori K, Shibanuma M, Nose K. Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res. 2004;64(20):7464–72.PubMed
104.
Zurück zum Zitat Allington TM, Galliher-Beckley AJ, Schiemann WP. Activated Abl kinase inhibits oncogenic transforming growth factor-beta signaling and tumorigenesis in mammary tumors. FASEB J. 2009;23(12):4231–43.PubMed Allington TM, Galliher-Beckley AJ, Schiemann WP. Activated Abl kinase inhibits oncogenic transforming growth factor-beta signaling and tumorigenesis in mammary tumors. FASEB J. 2009;23(12):4231–43.PubMed
105.
Zurück zum Zitat Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 2007;101(4):830–9.PubMed Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 2007;101(4):830–9.PubMed
106.
Zurück zum Zitat Faouzi S, Le Bail B, Neaud V, et al. Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol. 1999;30(2):275–84.PubMed Faouzi S, Le Bail B, Neaud V, et al. Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol. 1999;30(2):275–84.PubMed
107.
Zurück zum Zitat Petersen OW, Nielsen HL, Gudjonsson T, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol. 2003;162(2):391–402.PubMed Petersen OW, Nielsen HL, Gudjonsson T, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol. 2003;162(2):391–402.PubMed
108.
Zurück zum Zitat Ronnov-Jessen L, Petersen OW, Koteliansky VE, et al. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest. 1995;95(2):859–73.PubMed Ronnov-Jessen L, Petersen OW, Koteliansky VE, et al. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest. 1995;95(2):859–73.PubMed
109.
Zurück zum Zitat Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006. Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006.
110.
Zurück zum Zitat Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells. Invest Ophthalmol Vis Sci. 1999;40(9):2025–32.PubMed Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells. Invest Ophthalmol Vis Sci. 1999;40(9):2025–32.PubMed
111.
Zurück zum Zitat Li JH, Wang W, Huang XR, et al. Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. Am J Pathol. 2004;164(4):1389–97.PubMed Li JH, Wang W, Huang XR, et al. Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. Am J Pathol. 2004;164(4):1389–97.PubMed
112.
Zurück zum Zitat Nightingale J, Patel S, Suzuki N, et al. Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. J Am Soc Nephrol. 2004;15(1):21–32.PubMed Nightingale J, Patel S, Suzuki N, et al. Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. J Am Soc Nephrol. 2004;15(1):21–32.PubMed
113.
Zurück zum Zitat Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006;3(4):377–82.PubMed Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006;3(4):377–82.PubMed
114.
Zurück zum Zitat Moinfar F, Man YG, Arnould L, et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 2000;60(9):2562–6.PubMed Moinfar F, Man YG, Arnould L, et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 2000;60(9):2562–6.PubMed
115.
Zurück zum Zitat Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808.PubMed Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808.PubMed
116.
Zurück zum Zitat Kelemen LE, Sellers TA, Vachon CM. Can genes for mammographic density inform cancer aetiology? Nat Rev Cancer. 2008;8(10):812–23.PubMed Kelemen LE, Sellers TA, Vachon CM. Can genes for mammographic density inform cancer aetiology? Nat Rev Cancer. 2008;8(10):812–23.PubMed
117.
Zurück zum Zitat Bartow SA, Pathak DR, Mettler FA. Radiographic microcalcification and parenchymal patterns as indicators of histologic “high-risk” benign breast disease. Cancer. 1990;66(8):1721–5.PubMed Bartow SA, Pathak DR, Mettler FA. Radiographic microcalcification and parenchymal patterns as indicators of histologic “high-risk” benign breast disease. Cancer. 1990;66(8):1721–5.PubMed
118.
Zurück zum Zitat Boyd NF, Jensen HM, Cooke G, et al. Mammographic densities and the prevalence and incidence of histological types of benign breast disease. Reference Pathologists of the Canadian National Breast Screening Study. Eur J Cancer Prev. 2000;9(1):15–24.PubMed Boyd NF, Jensen HM, Cooke G, et al. Mammographic densities and the prevalence and incidence of histological types of benign breast disease. Reference Pathologists of the Canadian National Breast Screening Study. Eur J Cancer Prev. 2000;9(1):15–24.PubMed
119.
Zurück zum Zitat Bright RA, Morrison AS, Brisson J, et al. Relationship between mammographic and histologic features of breast tissue in women with benign biopsies. Cancer. 1988;61(2):266–71.PubMed Bright RA, Morrison AS, Brisson J, et al. Relationship between mammographic and histologic features of breast tissue in women with benign biopsies. Cancer. 1988;61(2):266–71.PubMed
120.
Zurück zum Zitat Buchanan JB, Weisberg BF, Sandoz JP, et al. Selected prognostic variables for mammographic parenchymal patterns. Cancer. 1981;47(9):2135–7.PubMed Buchanan JB, Weisberg BF, Sandoz JP, et al. Selected prognostic variables for mammographic parenchymal patterns. Cancer. 1981;47(9):2135–7.PubMed
121.
Zurück zum Zitat Urbanski S, Jensen HM, Cooke G, et al. The association of histological and radiological indicators of breast cancer risk. Br J Cancer. 1988;58(4):474–9.PubMed Urbanski S, Jensen HM, Cooke G, et al. The association of histological and radiological indicators of breast cancer risk. Br J Cancer. 1988;58(4):474–9.PubMed
122.
Zurück zum Zitat Wellings SR, Wolfe JN. Correlative studies of the histological and radiographic appearance of the breast parenchyma. Radiology. 1978;129(2):299–306.PubMed Wellings SR, Wolfe JN. Correlative studies of the histological and radiographic appearance of the breast parenchyma. Radiology. 1978;129(2):299–306.PubMed
123.
Zurück zum Zitat Heppner KJ, Matrisian LM, Jensen RA, et al. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996;149(1):273–82.PubMed Heppner KJ, Matrisian LM, Jensen RA, et al. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996;149(1):273–82.PubMed
124.
Zurück zum Zitat Del Casar JM, Gonzalez LO, Alvarez E, et al. Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumor stromal fibroblasts and those at the invasive front of breast carcinomas. Breast Cancer Res Treat. 2009;116(1):39–52.PubMed Del Casar JM, Gonzalez LO, Alvarez E, et al. Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumor stromal fibroblasts and those at the invasive front of breast carcinomas. Breast Cancer Res Treat. 2009;116(1):39–52.PubMed
125.
Zurück zum Zitat Vizoso FJ, Gonzalez LO, Corte MD, et al. Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer. 2007;96(6):903–11.PubMed Vizoso FJ, Gonzalez LO, Corte MD, et al. Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer. 2007;96(6):903–11.PubMed
126.
Zurück zum Zitat Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–27.PubMed Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–27.PubMed
127.
Zurück zum Zitat Ahmad A, Hanby A, Dublin E, et al. Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. Am J Pathol. 1998;152(3):721–8.PubMed Ahmad A, Hanby A, Dublin E, et al. Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. Am J Pathol. 1998;152(3):721–8.PubMed
128.
Zurück zum Zitat Lien HC, Hsiao YH, Lin YS, et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene. 2007;26(57):7859–71.PubMed Lien HC, Hsiao YH, Lin YS, et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene. 2007;26(57):7859–71.PubMed
129.
Zurück zum Zitat Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295(5564):2387–92.PubMed Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295(5564):2387–92.PubMed
130.
Zurück zum Zitat Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004;22(23):4683–90.PubMed Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004;22(23):4683–90.PubMed
131.
Zurück zum Zitat Miller KD, Gradishar W, Schuchter L, et al. A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol. 2002;13(8):1220–4.PubMed Miller KD, Gradishar W, Schuchter L, et al. A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol. 2002;13(8):1220–4.PubMed
132.
Zurück zum Zitat Miller KD, Saphner TJ, Waterhouse DM, et al. A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Clin Cancer Res. 2004;10(6):1971–5.PubMed Miller KD, Saphner TJ, Waterhouse DM, et al. A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Clin Cancer Res. 2004;10(6):1971–5.PubMed
133.
Zurück zum Zitat Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci. 2006;11:479–91.PubMed Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci. 2006;11:479–91.PubMed
134.
Zurück zum Zitat Martin MD, Matrisian LM. The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007;26(3–4):717–24.PubMed Martin MD, Matrisian LM. The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007;26(3–4):717–24.PubMed
135.
Zurück zum Zitat Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227–39.PubMed Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227–39.PubMed
136.
Zurück zum Zitat Montel V, Kleeman J, Agarwal D, et al. Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression. Cancer Res. 2004;64(5):1687–94.PubMed Montel V, Kleeman J, Agarwal D, et al. Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression. Cancer Res. 2004;64(5):1687–94.PubMed
137.
Zurück zum Zitat Gutierrez-Fernandez A, Fueyo A, Folgueras AR, et al. Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res. 2008;68(8):2755–63.PubMed Gutierrez-Fernandez A, Fueyo A, Folgueras AR, et al. Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res. 2008;68(8):2755–63.PubMed
138.
Zurück zum Zitat Fingleton B. MMPs as therapeutic targets-still a viable option? Semin Cell Dev Biol. 2008;19(1):61–8.PubMed Fingleton B. MMPs as therapeutic targets-still a viable option? Semin Cell Dev Biol. 2008;19(1):61–8.PubMed
139.
Zurück zum Zitat Saghatelian A, Jessani N, Joseph A, et al. Activity-based probes for the proteomic profiling of metalloproteases. Proc Natl Acad Sci U S A. 2004;101(27):10000–5.PubMed Saghatelian A, Jessani N, Joseph A, et al. Activity-based probes for the proteomic profiling of metalloproteases. Proc Natl Acad Sci U S A. 2004;101(27):10000–5.PubMed
140.
Zurück zum Zitat Fisher JF, Mobashery S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev. 2006;25(1):115–36.PubMed Fisher JF, Mobashery S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev. 2006;25(1):115–36.PubMed
141.
Zurück zum Zitat Rao BG. Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des. 2005;11(3):295–322.PubMed Rao BG. Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des. 2005;11(3):295–322.PubMed
142.
Zurück zum Zitat Bertini I, Calderone V, Cosenza M, et al. Conformational variability of matrix metalloproteinases: beyond a single 3D structure. Proc Natl Acad Sci U S A. 2005;102(15):5334–9.PubMed Bertini I, Calderone V, Cosenza M, et al. Conformational variability of matrix metalloproteinases: beyond a single 3D structure. Proc Natl Acad Sci U S A. 2005;102(15):5334–9.PubMed
143.
Zurück zum Zitat Matter H, Schudok M. Recent advances in the design of matrix metalloprotease inhibitors. Curr Opin Drug Discov Devel. 2004;7(4):513–35.PubMed Matter H, Schudok M. Recent advances in the design of matrix metalloprotease inhibitors. Curr Opin Drug Discov Devel. 2004;7(4):513–35.PubMed
144.
Zurück zum Zitat Moy FJ, Chanda PK, Chen J, et al. Impact of mobility on structure-based drug design for the MMPs. J Am Chem Soc. 2002;124(43):12658–9.PubMed Moy FJ, Chanda PK, Chen J, et al. Impact of mobility on structure-based drug design for the MMPs. J Am Chem Soc. 2002;124(43):12658–9.PubMed
145.
Zurück zum Zitat Jacobsen JA, Major Jourden JL, Miller MT, et al. To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta. 2010;1803(1):72–94.PubMed Jacobsen JA, Major Jourden JL, Miller MT, et al. To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta. 2010;1803(1):72–94.PubMed
146.
Zurück zum Zitat Ikejiri M, Bernardo MM, Meroueh SO, et al. Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A. J Org Chem. 2005;70(14):5709–12.PubMed Ikejiri M, Bernardo MM, Meroueh SO, et al. Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A. J Org Chem. 2005;70(14):5709–12.PubMed
147.
Zurück zum Zitat Lee MH, Rapti M, Knauper V, et al. Threonine 98, the pivotal residue of tissue inhibitor of metalloproteinases (TIMP)-1 in metalloproteinase recognition. J Biol Chem. 2004;279(17):17562–9.PubMed Lee MH, Rapti M, Knauper V, et al. Threonine 98, the pivotal residue of tissue inhibitor of metalloproteinases (TIMP)-1 in metalloproteinase recognition. J Biol Chem. 2004;279(17):17562–9.PubMed
148.
Zurück zum Zitat Lee MH, Rapti M, Murphy G. Unveiling the surface epitopes that render tissue inhibitor of metalloproteinase-1 inactive against membrane type 1-matrix metalloproteinase. J Biol Chem. 2003;278(41):40224–30.PubMed Lee MH, Rapti M, Murphy G. Unveiling the surface epitopes that render tissue inhibitor of metalloproteinase-1 inactive against membrane type 1-matrix metalloproteinase. J Biol Chem. 2003;278(41):40224–30.PubMed
149.
Zurück zum Zitat Meng Q, Malinovskii V, Huang W, et al. Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1’ residue of substrate. J Biol Chem. 1999;274(15):10184–9.PubMed Meng Q, Malinovskii V, Huang W, et al. Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1’ residue of substrate. J Biol Chem. 1999;274(15):10184–9.PubMed
150.
Zurück zum Zitat Nagase H, Brew K. Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors. Biochem Soc Symp 2003;(70):201–12. Nagase H, Brew K. Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors. Biochem Soc Symp 2003;(70):201–12.
151.
Zurück zum Zitat Wei S, Chen Y, Chung L, et al. Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors. J Biol Chem. 2003;278(11):9831–4.PubMed Wei S, Chen Y, Chung L, et al. Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors. J Biol Chem. 2003;278(11):9831–4.PubMed
152.
Zurück zum Zitat Williamson RA, Hutton M, Vogt G, et al. Tyrosine 36 plays a critical role in the interaction of the AB loop of tissue inhibitor of metalloproteinases-2 with matrix metalloproteinase-14. J Biol Chem. 2001;276(35):32966–70.PubMed Williamson RA, Hutton M, Vogt G, et al. Tyrosine 36 plays a critical role in the interaction of the AB loop of tissue inhibitor of metalloproteinases-2 with matrix metalloproteinase-14. J Biol Chem. 2001;276(35):32966–70.PubMed
153.
Zurück zum Zitat Lee MH, Atkinson S, Rapti M, et al. The activity of a designer tissue inhibitor of metalloproteinases (TIMP)-1 against native membrane type 1 matrix metalloproteinase (MT1-MMP) in a cell-based environment. Cancer Lett. 2009. Lee MH, Atkinson S, Rapti M, et al. The activity of a designer tissue inhibitor of metalloproteinases (TIMP)-1 against native membrane type 1 matrix metalloproteinase (MT1-MMP) in a cell-based environment. Cancer Lett. 2009.
154.
Zurück zum Zitat Devy L, Huang L, Naa L, et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 2009;69(4):1517–26.PubMed Devy L, Huang L, Naa L, et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 2009;69(4):1517–26.PubMed
155.
Zurück zum Zitat DeLano WL. The PyMOL Molecular Graphics System. In. San Carlos, CA, USA: DeLano Scientific. 2002. DeLano WL. The PyMOL Molecular Graphics System. In. San Carlos, CA, USA: DeLano Scientific. 2002.
156.
Zurück zum Zitat Morgunova E, Tuuttila A, Bergmann U, et al. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci U S A. 2002;99(11):7414–9.PubMed Morgunova E, Tuuttila A, Bergmann U, et al. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci U S A. 2002;99(11):7414–9.PubMed
Metadaten
Titel
Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer
verfasst von
Evette S. Radisky
Derek C. Radisky
Publikationsdatum
01.06.2010
Verlag
Springer US
Erschienen in
Journal of Mammary Gland Biology and Neoplasia / Ausgabe 2/2010
Print ISSN: 1083-3021
Elektronische ISSN: 1573-7039
DOI
https://doi.org/10.1007/s10911-010-9177-x

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