Skip to main content

Advertisement

SpringerLink
Log in

Expression of metalloproteases and their inhibitors in different histological types of breast cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Metalloproteases (MMPs) and their tissue inhibitors of metalloproteases (TIMPs) are involved in several key aspects of tumoral growth, invasion and metastasis. The purpose of this study was to characterize on how the different histological types of breast cancer differ in the expression of several components of this enzymatic system.

Methods

An immunohistochemical study was performed in 50 ductal, 23 lobular, 14 mucinous, 7 tubular, 4 papillary and 5 medullary invasive carcinomas, using tissue arrays and specific antibodies against 7 MMPs and 3 tisullar TIMPs. Staining results were categorized by means of a specific software program (score values).

Results

Carcinomas of the ductal type showed higher score values for MMPs and TIMPs than the other histological types; whereas mucinous carcinomas had lower scores values for expressions of the majority of these proteins. Stromal fibroblasts were more frequently positive for MMP-1, -7 and -13 and TIMP-1 and -3, when present in carcinomas of the ductal type than in other histological types of breast carcinomas. Stromal mononuclear inflammatory cells were more frequently positive for MMP-1 and TIMP-3, but more often negative for MMP-7, -9 and -11, when located in carcinomas of the ductal type than in other histological types of breast carcinomas.

Conclusions

We found variations in MMP/TIMP expressions among the different histological subtypes of breast carcinomas suggesting differences in their tumor pathophysiology

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155168

    Google Scholar 

  • Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC (1999) Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 79:1347–1355

    Article  CAS  PubMed  Google Scholar 

  • Bedner E, Harezga B, Osborn M, Domagala W (1995) Cathepsin D in invasive ductal NOS, medullary, lobular and mucinous breast carcinoma. An immunohistochemical study. Pol J Pathol 46:11–15

    CAS  PubMed  Google Scholar 

  • Blot E, Chen W, Vasse M, Paysant J, Denoyelle C, Pille JY, Vincent L, Vannier JP, Soria J, Soria C (2003) Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness. Br J Cancer 88:1207–1212

    Article  CAS  PubMed  Google Scholar 

  • Claus EB, Risch N, Thompson WD, Carter D (1993) Relationship between breast histopathology and family history of breast cancer. Cancer 71:147–153

    Article  CAS  PubMed  Google Scholar 

  • Coradini D, Pellizzaro C, Veneroni S, Ventura L, Daidone MG (2002) Infiltrating ductal and lobular breast carcinomas are characterised by different interrelationships among markers related to angiogenesis and hormone dependence. Br J Cancer 87:1105–1111

    Article  CAS  PubMed  Google Scholar 

  • Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD (1998) Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:6845–6852

    CAS  PubMed  Google Scholar 

  • Dixon AR, Ellis IO, Elston CW, Blamey RW (1991) A comparison of the clinical metastatic patterns of invasive lobular and ductal carcinomas of the breast. Br J Cancer 63:634–635

    CAS  PubMed  Google Scholar 

  • Dong Z, Kumar R, Yang X, Fidler IJ (1997) Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88:801–810

    Article  CAS  PubMed  Google Scholar 

  • du Toit RS, Locker AP, Ellis IO, Elston CW, Nicholson RI, Robertson JF, Blamey RW (1991) An evaluation of differences in prognosis, recurrence patterns and receptor status between invasive lobular and other invasive carcinomas of the breast. Eur J Surg Oncol 17:251–257

    CAS  PubMed  Google Scholar 

  • Duffy MJ, Maguire TM, Hill A, McDermott E, O’Higgins N (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2:252–257

    Article  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  PubMed  Google Scholar 

  • Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaisse J (2000) Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett 486:247–251

    Article  CAS  PubMed  Google Scholar 

  • Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM (2001) Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia 3:459–468

    Article  CAS  PubMed  Google Scholar 

  • Fisher ER, Anderson S, Tan-Chiu E, Fisher B, Eaton L, Wolmark N (2001) Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol-06. Cancer 91:1679–1687

    Article  CAS  PubMed  Google Scholar 

  • Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22:207–219

    Article  CAS  PubMed  Google Scholar 

  • Gamel JW, Meyer JS, Feuer E, Miller BA (1996) The impact of stage and histology on the long-term clinical course of 163, 808 patients with breast carcinoma. Cancer 77:1459–1464

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez LO, Pidal I, Junquera S, Corte MD, Vazquez J, Rodriguez JC, Lamelas ML, Merino AM, Garcia-Muniz JL, Vizoso FJ (2007) Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse. Br J Cancer 97:957–963

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez L, Corte MD, Vazquez J, Junquera S, Sanchez R, Viña A, Rodriguez J, Lamelas ML, Vizoso F (2008) Study of matrix metalloproteinases and their tissular inhibitors in ductal “in situ” carcinomas of the breast. Histopathology 53(4):403–415

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21:2245–2252

    Article  CAS  PubMed  Google Scholar 

  • Jiang WG, Davies G, Martin TA, Parr C, Watkins G, Mason MD, Mokbel K, Mansel RE (2005) Targeting matrilysin and its impact on tumor growth in vivo: the potential implications in breast cancer therapy. Clin Cancer Res 11:6012–6019

    Article  CAS  PubMed  Google Scholar 

  • Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189:161168

    Article  Google Scholar 

  • Kim DH, Yoon DS, Dooley WC, Nam ES, Ryu JW, Jung KC, Park HR, Sohn JH, Shin HS, Park YE (2003) Association of maspin expression with the high histological grade and lymphocyte-rich stroma in early-stage breast cancer. Histopathology 42:37–42

    Article  CAS  PubMed  Google Scholar 

  • Kitchen PR, Smith TH, Henderson MA, Goldhirsch A, Castiglione-Gertsch M, Coates AS, Gusterson B, Brown RW, Gelber RD, Collins JP (2001) Tubular carcinoma of the breast: prognosis and response to adjuvant systemic therapy. ANZ J Surg 71:27–31

    Article  CAS  PubMed  Google Scholar 

  • Klausner RD (2002) The fabric of cancer cell biology-Weaving together the strands. Cancer Cell 1:3–10

    Article  CAS  PubMed  Google Scholar 

  • Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550

    Article  CAS  PubMed  Google Scholar 

  • Korhonen T, Huhtala H, Holli K (2004) A comparison of the biological and clinical features of invasive lobular and ductal carcinomas of the breast. Breast Cancer Res Treat 85:23–29

    Article  CAS  PubMed  Google Scholar 

  • Lakhani SR, Gusterson BA, Jacquemier J, Sloane JP, Anderson TJ, van de Vijver MJ, Venter D, Freeman A, Antoniou A, McGuffog L, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Futreal PA, Peto J, Stoppa-Lyonnet D, Bignon YJ, Stratton MR (2000) The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 6:782–789

    CAS  PubMed  Google Scholar 

  • Lee SJ, Yoo HJ, Bae YS, Kim HJ, Lee ST (2003) TIMP-1 inhibits apoptosis in breast carcinoma cells via a pathway involving pertussis toxin-sensitive G protein and c-Src. Biochem Biophys Res Commun 312:1196–1201

    Article  CAS  PubMed  Google Scholar 

  • Li CI, Uribe DJ, Daling JR (2005) Clinical characteristics of different histologic types of breast cancer. Br J Cancer 93:1046–1052

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Manes S, Llorente M, Lacalle RA, Gomez-Mouton C, Kremer L, Mira E, Martinez AC (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem 274:6935–6945

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  • Nielsen BS, Rank F, Lopez JM, Balbin M, Vizoso F, Lund LR, Dano K, Lopez-Otin C (2001) Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res 61:7091–7100

    CAS  PubMed  Google Scholar 

  • Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114:111–118

    CAS  PubMed  Google Scholar 

  • Northridge ME, Rhoads GG, Wartenberg D, Koffman D (1997) The importance of histologic type on breast cancer survival. J Clin Epidemiol 50:283–290

    Article  CAS  PubMed  Google Scholar 

  • Parker RL, Huntsman DG, Lesack DW, Cupples JB, Grant DR, Akbari M, Gilks CB (2002) Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol 117:723–728

    Article  PubMed  Google Scholar 

  • Pedersen L, Holck S, Schiodt T, Zedeler K, Mouridsen HT (1994) Medullary carcinoma of the breast, prognostic importance of characteristic histopathological features evaluated in a multivariate Cox analysis. Eur J Cancer 30A:1792–1797

    Article  CAS  PubMed  Google Scholar 

  • Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S, Trumper L, Binder C (2006) Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci USA 103:5454–5459

    Article  CAS  PubMed  Google Scholar 

  • Ree AH, Florenes VA, Berg JP, Maelandsmo GM, Nesland JM, Fodstad O (1997) High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res 3:1623–1628

    CAS  PubMed  Google Scholar 

  • Reed W, Hannisdal E, Boehler PJ, Gundersen S, Host H, Marthin J (2000) The prognostic value of p53 and c-erb B-2 immunostaining is overrated for patients with lymph node negative breast carcinoma: a multivariate analysis of prognostic factors in 613 patients with a follow-up of 14–30 years. Cancer 88:804–813

    Article  CAS  PubMed  Google Scholar 

  • Rey MJ, Fernandez PL, Jares P, Munoz M, Nadal A, Peiro N, Nayach I, Mallofre C, Muntane J, Campo E, Estape J, Cardesa A (1998) p21WAF1/Cip1 is associated with cyclin D1CCND1 expression and tubular differentiation but is independent of p53 overexpression in human breast carcinoma. J Pathol 184:265–271

    Article  CAS  PubMed  Google Scholar 

  • Rifkin DB, Mazzieri R, Munger JS, Noguera I, Sung J (1999) Proteolytic control of growth factor availability. APMIS 107:80–85

    Article  CAS  PubMed  Google Scholar 

  • Sastre-Garau X, Jouve M, Asselain B, Vincent-Salomon A, Beuzeboc P, Dorval T, Durand JC, Fourquet A, Pouillart P (1996) Infiltrating lobular carcinoma of the breast. Clinicopathologic analysis of 975 cases with reference to data on conservative therapy and metastatic patterns. Cancer 77:113–120

    Article  CAS  PubMed  Google Scholar 

  • Schrohl AS, Holten-Andersen MN, Peters HA, Look MP, Meijer-van Gelder ME, Klijn JG, Brunner N, Foekens JA (2004) Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Cancer Res 10:2289–2298

    Article  CAS  PubMed  Google Scholar 

  • Sloane BF, Yan S, Podgorski I, Linebaugh BE, Cher ML, Mai J, Cavallo-Medved D, Sameni M, Dosescu J, Moin K (2005) Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment. Semin Cancer Biol 15:149–157

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Stetler-Stevenson WG (1999) Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103:1237–1241

    Article  CAS  PubMed  Google Scholar 

  • Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI (1995) Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 270:5331–5338

    Article  CAS  PubMed  Google Scholar 

  • Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T (2003) Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma. Br J Cancer 89:1270–1275

    Article  CAS  PubMed  Google Scholar 

  • Turk V, Kos J, Turk B (2004) Cysteine cathepsins (proteases)—on the main stage of cancer? Cancer Cell 5:409–410

    Article  CAS  PubMed  Google Scholar 

  • Vizoso FJ, Gonzalez LO, Corte MD, Rodriguez JC, Vazquez J, Lamelas ML, Junquera S, Merino AM, Garcia-Muniz JL (2007) Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer 96:903–911

    Article  CAS  PubMed  Google Scholar 

  • Wellings SR, Jensen HM, Marcum RG (1975) An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst 55:231–273

    CAS  PubMed  Google Scholar 

  • Winchester DJ, Chang HR, Graves TA, Menck HR, Bland KI, Winchester DP (1998) A comparative analysis of lobular and ductal carcinoma of the breast: presentation, treatment, and outcomes. J Am Coll Surg 186:416–422

    Article  CAS  PubMed  Google Scholar 

  • Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049

    Article  CAS  PubMed  Google Scholar 

  • Wurtz SO, Schrohl AS, Sorensen NM, Lademann U, Christensen IJ, Mouridsen H, Brunner N (2005) Tissue inhibitor of metalloproteinases-1 in breast cancer. Endocr Relat Cancer 12:215–227

    Article  CAS  PubMed  Google Scholar 

  • Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro s/n, 33290, Gijón, Asturias, Spain

    J. M. Del Casar, S. González-Reyes, L. O. González, J. M. González, S. Junquera, M. Bongera, M. F. García, A. Andicoechea & F. J. Vizoso

  2. Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain

    J. M. Del Casar, S. González-Reyes, L. O. González, A. Andicoechea & F. J. Vizoso

  3. Servicio de Cirugía General, Fundación Hospital de Jove, Gijón, Spain

    J. M. Del Casar, A. Andicoechea & F. J. Vizoso

  4. Servicio de Anatomía Patológica, Fundación Hospital de Jove, Gijón, Spain

    L. O. González

  5. Servicio de Cirugía General, Hospital Virgen de los Lirios, Alcoy, Spain

    C. Serra

Authors
  1. J. M. Del Casar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. González-Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. O. González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. M. González
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Junquera
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Bongera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. F. García
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Andicoechea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Serra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F. J. Vizoso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. J. Vizoso.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Del Casar, J.M., González-Reyes, S., González, L.O. et al. Expression of metalloproteases and their inhibitors in different histological types of breast cancer. J Cancer Res Clin Oncol 136, 811–819 (2010). https://doi.org/10.1007/s00432-009-0721-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0721-2

Keywords

Search

Navigation