Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

Oncogene volume 31, pages 480–493 (2012)Cite this article

Abstract

As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminal-like breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Bao W, Strömblad S . (2004). Integrin alphav-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen. J Cell Biol 167: 745–756.

    Article  CAS  Google Scholar 

  • Barbolina MV, Stack MS . (2008). Membrane type 1-matrix metalloproteinase: substrate diversity in pericellular proteolysis. Semin Cell Dev Biol 19: 24–33.

    Article  CAS  Google Scholar 

  • Barkan D, El Touny LH, Michalowski AM, Smith JA, Chu I, Davis AS et al. (2010). Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res 70: 5706–5716.

    Article  CAS  Google Scholar 

  • Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noel A et al. (2006). Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene 25: 4975–4985.

    Article  CAS  Google Scholar 

  • Birkedal-Hansen H . (1987). Catabolism and turnover of collagens: collagenases. Methods Enzymol 144: 140–171.

    Article  CAS  Google Scholar 

  • Bissell MJ, Rizki A, Mian IS . (2003). Tissue architecture: the ultimate regulator of breast epithelial function. Curr Opin Cell Biol 15: 753–762.

    Article  CAS  Google Scholar 

  • Blick T, Hugo H, Widodo E, Waltham M, Pinto C, Mani SA et al. (2010). Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia 15: 235–252.

    Article  Google Scholar 

  • Butler GS, Dean RA, Tam EM, Overall CM . (2008). Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: dynamics of membrane type 1 matrix metalloproteinase-mediated membrane protein shedding. Mol Cell Biol 28: 4896–4914.

    Article  CAS  Google Scholar 

  • Chinnadurai G, Vijayalingam S, Rashmi R . (2008). BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes. Oncogene 27 (Suppl 1): S20–S29.

    Article  CAS  Google Scholar 

  • Eccles SA, Box GM, Court WJ, Bone EA, Thomas W, Brown PD . (1996). Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res 56: 2815–2822.

    CAS  PubMed  Google Scholar 

  • Egeblad M, Werb Z . (2002). New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161–174.

    Article  CAS  Google Scholar 

  • Figueira RC, Gomes LR, Neto JS, Silva FC, Silva ID, Sogayar MC . (2009). Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential. BMC Cancer 9: 20.

    Article  Google Scholar 

  • Fujisaki H, Hattori S . (2002). Keratinocyte apoptosis on type I collagen gel caused by lack of laminin 5/10/11 deposition and Akt signaling. Exp Cell Res 280: 255–269.

    Article  CAS  Google Scholar 

  • Galluzzi L, Aaronson SA, Abrams J, Alnemri ES, Andrews DW, Baehrecke EH et al. (2009). Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 16: 1093–1107.

    Article  CAS  Google Scholar 

  • Giam M, Huang DC, Bouillet P . (2008). BH3-only proteins and their roles in programmed cell death. Oncogene 27 (Suppl 1): S128–S136.

    Article  CAS  Google Scholar 

  • Gingras D, Béliveau R . (2010). Emerging concepts in the regulation of membrane-type 1 matrix metalloproteinase activity. Biochim Biophys Acta 1803: 142–150.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2011). Hallmarks of cancer: the next generation. Cell 144: 646–674.

    Article  CAS  Google Scholar 

  • Henriet P, Zhong ZD, Brooks PC, Weinberg KI, DeClerck YA . (2000). Contact with fibrillar collagen inhibits melanoma cell proliferation by up-regulating p27KIP1. Proc Natl Acad Sci USA 97: 10026–10031.

    Article  CAS  Google Scholar 

  • Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ . (1998). Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95: 365–377.

    Article  CAS  Google Scholar 

  • Hotary K, Allen E, Punturieri A, Yana I, Weiss SJ . (2000). Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J Cell Biol 149: 1309–1323.

    Article  CAS  Google Scholar 

  • Hotary K, Li XY, Allen E, Stevens SL, Weiss SJ . (2006). A cancer cell metalloprotease triad regulates the basement membrane transmigration program. Genes Dev 20: 2673–2686.

    Article  CAS  Google Scholar 

  • Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ . (2003). Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114: 33–45.

    Article  CAS  Google Scholar 

  • Hotary KB, Yana I, Sabeh F, Li XY, Holmbeck K, Birkedal-Hansen H et al. (2002). Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J Exp Med 195: 295–308.

    Article  CAS  Google Scholar 

  • Hur J, Chesnes J, Coser KR, Lee RS, Geck P, Isselbacher KJ et al. (2004). The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proc Natl Acad Sci USA 101: 2351–2356.

    Article  CAS  Google Scholar 

  • Hynes RO . (2009). The extracellular matrix: not just pretty fibrils. Science 326: 1216–1219.

    Article  CAS  Google Scholar 

  • Kalluri R, Zeisberg M . (2006). Fibroblasts in cancer. Nat Rev Cancer 6: 392–401.

    Article  CAS  Google Scholar 

  • Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J et al. (2009). Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One 4: e6146.

    Article  Google Scholar 

  • Kauppila S, Stenback F, Risteli J, Jukkola A, Risteli L . (1998). Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J Pathol 186: 262–268.

    Article  CAS  Google Scholar 

  • Kessenbrock K, Plaks V, Werb Z . (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141: 52–67.

    Article  CAS  Google Scholar 

  • Kim TY, Zhong S, Fields CR, Kim JH, Robertson KD . (2006). Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. Cancer Res 66: 7490–7501.

    Article  CAS  Google Scholar 

  • Koshikawa N, Mizushima H, Minegishi T, Eguchi F, Yotsumoto F, Nabeshima K et al. (2011). Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. Cancer Sci 102: 111–116.

    Article  CAS  Google Scholar 

  • Lehti K, Valtanen H, Wickstrom SA, Lohi J, Keski-Oja J . (2000). Regulation of membrane-type-1 matrix metalloproteinase activity by its cytoplasmic domain. J Biol Chem 275: 15006–15013.

    Article  CAS  Google Scholar 

  • Liotta LA, Kohn EC . (2001). The microenvironment of the tumour-host interface. Nature 411: 375–379.

    Article  CAS  Google Scholar 

  • Lomonosova E, Ryerse J, Chinnadurai G . (2009). BAX/BAK-independent mitoptosis during cell death induced by proteasome inhibition? Mol Cancer Res 7: 1268–1284.

    Article  CAS  Google Scholar 

  • Lopez-Otin C, Hunter T . (2010). The regulatory crosstalk between kinases and proteases in cancer. Nat Rev Cancer 10: 278–292.

    Article  CAS  Google Scholar 

  • Mathai JP, Germain M, Shore GC . (2005). BH3-only BIK regulates BAX, BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. J Biol Chem 280: 23829–23836.

    Article  CAS  Google Scholar 

  • McGowan PM, Duffy MJ . (2008). Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database. Ann Oncol 19: 1566–1572.

    Article  CAS  Google Scholar 

  • Mizushima H, Wang X, Miyamoto S, Mekada E . (2009). Integrin signal masks growth-promotion activity of HB-EGF in monolayer cell cultures. J Cell Sci 122: 4277–4286.

    Article  CAS  Google Scholar 

  • Montgomery AM, Reisfeld RA, Cheresh DA . (1994). Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci USA 91: 8856–8860.

    Article  CAS  Google Scholar 

  • Morrison CJ, Overall CM . (2006). TIMP independence of matrix metalloproteinase (MMP)-2 activation by membrane type 2 (MT2)-MMP is determined by contributions of both the MT2-MMP catalytic and hemopexin C domains. J Biol Chem 281: 26528–26539.

    Article  CAS  Google Scholar 

  • Nagase H, Visse R, Murphy G . (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562–573.

    Article  CAS  Google Scholar 

  • Naumann U, Schmidt F, Wick W, Frank B, Weit S, Gillissen B et al. (2003). Adenoviral natural born killer gene therapy for malignant glioma. Hum Gene Ther 14: 1235–1246.

    Article  CAS  Google Scholar 

  • Noël A, Jost M, Maquoi E . (2008). Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol 19: 52–60.

    Article  Google Scholar 

  • Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y . (1997). Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 272: 2446–2451.

    Article  CAS  Google Scholar 

  • Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P et al. (1995). Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA 92: 2730–2734.

    Article  CAS  Google Scholar 

  • Ota I, Li XY, Hu Y, Weiss SJ . (2009). Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci USA 106: 20318–20323.

    Article  CAS  Google Scholar 

  • Perumal S, Antipova O, Orgel JP . (2008). Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis. Proc Natl Acad Sci USA 105: 2824–2829.

    Article  CAS  Google Scholar 

  • Polyak K, Weinberg RA . (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9: 265–273.

    Article  CAS  Google Scholar 

  • Rodríguez D, Morrison CJ, Overall CM . (2010). Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 1803: 39–54.

    Article  Google Scholar 

  • Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K et al. (2005). Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11: 5678–5685.

    Article  CAS  Google Scholar 

  • Sabeh F, Li XY, Saunders TL, Rowe RG, Weiss SJ . (2009a). Secreted versus membrane-anchored collagenases: relative roles in fibroblast-dependent collagenolysis and invasion. J Biol Chem 284: 23001–23011.

    Article  CAS  Google Scholar 

  • Sabeh F, Ota I, Holmbeck K, Birkedal-Hansen H, Soloway P, Balbin M et al. (2004). Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol 167: 769–781.

    Article  CAS  Google Scholar 

  • Sabeh F, Shimizu-Hirota R, Weiss SJ . (2009b). Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J Cell Biol 185: 11–19.

    Article  CAS  Google Scholar 

  • Sarri D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J . (2008). Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68: 989–997.

    Article  Google Scholar 

  • Sato H, Takino T, Miyamori H . (2005). Roles of membrane-type matrix metalloproteinase-1 in tumor invasion and metastasis. Cancer Sci 96: 212–217.

    Article  CAS  Google Scholar 

  • Sodek KL, Brown TJ, Ringuette MJ . (2008). Collagen I but not Matrigel matrices provide an MMP-dependent barrier to ovarian cancer cell penetration. BMC Cancer 8: 223.

    Article  Google Scholar 

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. (2001). Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98: 10869–10874.

    Article  CAS  Google Scholar 

  • Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, Gilles C et al. (2002). MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 16: 555–564.

    Article  CAS  Google Scholar 

  • Sounni NE, Roghi C, Chabottaux V, Janssen M, Munaut C, Maquoi E et al. (2004). Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases. J Biol Chem 279: 13564–13574.

    Article  CAS  Google Scholar 

  • Sternlicht MD, Werb Z . (2001). How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17: 463–516.

    Article  CAS  Google Scholar 

  • Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S et al. (2006). Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ 13: 619–627.

    Article  CAS  Google Scholar 

  • Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J et al. (2010). Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA 107: 15449–15454.

    Article  CAS  Google Scholar 

  • Yamada KM, Cukierman E . (2007). Modeling tissue morphogenesis and cancer in 3D. Cell 130: 601–610.

    Article  CAS  Google Scholar 

  • Zou Y, Peng H, Zhou B, Wen Y, Wang SC, Tsai EM et al. (2002). Systemic tumor suppression by the proapoptotic gene bik. Cancer Res 62: 8–12.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M Fringuellini, P Gavitelli, E Konradovski and N Lefin for their excellent technical assistance. This work was supported by grants from the FP7-HEALTH-2007-A Proposal No 201279 ‘MICROENVIMET’, the Fonds de la Recherche Scientifique Médicale, the Fonds de la Recherche Scientifique - FNRS (FRS-FNRS, Belgium), the Foundation against Cancer (foundation of public interest, Belgium), the CGRI-FNRS-INSERM Coopération, the Fonds spéciaux de la Recherche (University of Liège), the Centre Anticancéreux près l’Université de Liège, the Fonds Léon Fredericq (University of Liège), the Direction Générale Opérationnelle de l’Economie, de l’Emploi et de la Recherche from the SPW (Région Wallonne, Belgium), the Fonds Social Européen (FSE, Belgium), the Fonds d’Investissements de la Recherche Scientifique (FIRS, CHU Liège, Belgium), the Interuniversity Attraction Poles Program - Belgian Science Policy (Brussels, Belgium). EM is a Research Associate from the F.R.S.-FNRS (Belgium).

Author information

Authors and Affiliations

  1. Laboratory of Tumor and Developmental Biology, GIGA-Cancer, Institute of Pathology, University of Liège, Liège, Belgium

    E Maquoi, D Assent, J Detilleux, C Pequeux, J-M Foidart & A Noël

Authors
  1. E Maquoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Assent
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Detilleux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Pequeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J-M Foidart
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Noël
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Maquoi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maquoi, E., Assent, D., Detilleux, J. et al. MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis. Oncogene 31, 480–493 (2012). https://doi.org/10.1038/onc.2011.249

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.249

Keywords

This article is cited by

Search

Advanced search

Quick links