Abstract
The expression of matrix metalloproteinases (MMPs) with type IV collagenase activity has been associated with tumour invasion and metastatic potential in experimental models. We studied whether the cellular localization of MMP expression provides useful information on tumour behaviour in human breast cancer.
Immunohistochemistry and non-radioisotopic-detected in situ hybridization were used to study protein and mRNA expression profiles for MMPs-2, -3 and -9 in paraffin sections of 70 invasive breast carcinomas.
Protein and mRNA expression of the MMPs was observed in tumour as well as in peritumoural stromal cells. MMP protein expression was increased at the invasive border (p < 0.05). Grade 3 carcinomas expressed MMP-2 mRNA in significantly more tumour cells than grade 2 carcinomas (p = 0.006). Ductal carcinomas with an extensive intraductal component were characterized by the lowest percentages of MMPs-2 and -3 mRNA expressing peritumoural stromal cells (p < 0.05). No correlation was observed between MMP protein/mRNA expression and pTNM classification.
In conclusion our results indicate that the expression of MMPs is associated with tumour behaviour. The correlation of MMPs-2 and -3 expression in peritumoural stromal cells with tumour type, shown for the first time, suggests that transcriptional regulation of these MMPs in stromal cells is important for the growth pattern of breast cancer.
Similar content being viewed by others
References
Alessandro R, Minafra S, Pucci-Minafra I, Onisto M, Garbisa S, Melchiori A, Tetlow L, Woolley DE (1993) Metalloproteinase and TIMP expression by the human breast carcinoma cell line 8701-BC. Int J Cancer 55: 250-255.
Alvarez OA, Carmichael DF, DeClerck YA (1990) Inhibition of col-lagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82: 589-595.
Birembaut P, Caron Y, Adnet JJ, Foidart JM (1985) Usefulness of basement membrane markers in tumoural pathology. J Pathol 145: 283-296.
Brown PD, Bloxidge RE, Anderson E, Howell A (1993) Expression of activated gelatinase in human invasive breast carcinoma. Clin Exp Metastasis 11: 183-189.
Brummer O, Athar S, Riethdorf L, Loning T, Herbst H (1999) Matrix-metalloproteinases 1, 2, and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: An in situ hybridization study. Virchows Arch 435: 566-573.
Cam Y, Bellon G, Poulin G, Caron Y, Birembaut P (1984) Distribution of type IV collagen in benign and malignant epithelial proliferations. An indirect immunofluorescence study on the breasts, the lungs, and the skin. Invasion Metastasis 4: 61-72.
Chambers AF, Matrisian LM(1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260-1270.
Clavel C, Polette M, Doco M, Binninger I, Birembaut P (1992) Immunolocalization of matrix metallo-proteinases and their tissue inhibitor in human mammary pathology. Bull Cancer 79: 261-270.
Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481-490.
Daidone MG, Silvestrini R, D'Errico A, Di Fronzo G, Benini E, Mancini AM, Garbisa S, Liotta LA, Grigioni WF (1991) Laminin receptors, collagenase IV and prognosis in node-negative breast cancers. Int J Cancer 48: 529-532.
Dalberg K, Eriksson E, Enberg U, Kjellman M, Backdahl M (2000) Gelatinase A, membrane type 1 matrix metalloproteinase, and extracel-lular matrix metalloproteinase inducer mRNA expression: Correlation with invasive growth of breast cancer. World J Surg 24: 334-340.
Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR (1993) Activity of type IV collagenases in benign and malignant breast disease. Br J Cancer 67: 1126-1131
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 19: 403-410.
Garbett EA, Reed MW, Stephenson TJ, Brown NJ (2000) Proteolysis in human breast cancer. Mol Pathol 53: 99-106.
Garbisa S, Pozzatti R, Muschel RJ, Saffiotti U, Ballin M, Goldfarb RH, Khoury G, Liotta LA (1987) Secretion of type IV collagenolytic protease and metastatic phenotype: Induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. Cancer Res 47: 1523-1528.
Giambernardi TA, Grant GM, Taylor GP, Hay RJ, Maher VM, McCormick JJ, Klebe RJ (1998) Overviewof matrix metalloproteinase expression in cultured human cells. Matrix Biol 16: 483-496.
Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH(1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149: 273-282.
Ioachim EE, Kamina S, Kontostolis M, Agnantis NJ (1997) Immunohistochemical expression of cathepsin D in correlation with extracellular matrix component, steroid receptor status and prolifera-tive indices in breast cancer. Virchows Arch 431: 311-316.
Ioachim EE, Athanassiadou SE, Kamina S, Carassavoglou K, Agnantis NJ (1998) Matrix metalloproteinase expression in human breast cancer: An immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. Anticancer Res 18: 1665-1670.
Iwata H, Kobayashi S, Iwase H, Masaoka A, Fujimoto N, Okada Y(1996) Production of matrix metalloproteinases and tissue inhibitors of met-alloproteinases in human breast carcinomas. Jpn J Cancer Res 87: 602-611.
Jones JL, Royall JE, Walker RA (1996) E-cadherin relates to EGFR expression and lymph node metastasis in primary breast carcinoma. Br J Cancer 74: 1237-1241.
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: 161-168.
Lebeau A, Nerlich AG, Sauer U, Lichtinghagen R, Lohrs U(1999) Tissue distribution of major matrix metalloproteinases and their transcripts in human breast carcinomas. Anticancer Res 19: 4257-4264.
Lichtinghagen R, Helmbrecht T, Arndt B, Boker KH (1995) Expression pattern of matrix metalloproteinases in human liver. Eur J Clin Chem Clin Biochem 33: 65-71.
Llorens A, Rodrigo I, Lopez-Barcons L, Gonzalez-Garrigues M, Lozano E, Vinyals A, Quintanilla M, Cano A, Fabra A (1998) Down-regulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloproteinase-9 gelatinase expression. Lab Invest 78: 1131-1142.
Moll R, Mitze M, Frixen UH, Birchmeier W (1993) Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am J Pathol 143: 1731-1742.
Nakajima M, Welch DR, Belloni PN, Nicolson GL(1987) Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res 47: 4869-4876.
Nakopoulou L, Giannopoulou I, Gakiopoulou H, Liapis H, Tzonou A, Davaris PS (1999) Matrix metalloproteinase-1 and-3 in breast cancer: Correlation with progesterone receptors and other clinicopathologic features. Hum Pathol 30: 436-442.
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM (2000) Matrix metalloproteinases: Biologic activity and clinical implications. J Clin Oncol 18: 1135-1149.
Nielsen BS, Sehested M, Kjeldsen L, Borregaard N, Rygaard J, Dano K (1997) Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab Invest 77: 345-355.
Pacheco MM, Mourao M, Mantovani EB, Nishimoto IN, Brentani MM (1998) Expression of gelatinases Aand B, stromelysin-3 and matrilysin genes in breast carcinomas: Clinico-pathological correlations. Clin Exp Metastasis 16: 577-585.
Polette M, Gilbert N, Stas I, Nawrocki B, Noel A, Remacle A, Stetler-Stevenson WG, Birembaut P, Foidart M (1994) Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using con-focal microscopy. Virchows Arch 424: 641-645.
Ponder BA (2001) Cancer genetics. Nature 411: 336-341.
Poulsom R, Hanby AM, Pignatelli M, Jeffery RE, Longcroft JM, Rogers L, Stamp GW (1993) Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J Clin Pathol 46: 429-436.
Remacle AG, Noel A, Duggan C, McDermott E, O'Higgins N, Foidart JM, Duffy MJ (1998) Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer. Br J Cancer 77: 926-931.
Ries C, Lottspeich F, Dittmann KH, Petrides PE (1996) HL-60 leukemia cells produce an autocatalytically truncated form of matrix metalloproteinase-9 with impaired sensitivity to inhibition by tissue inhibitors of metalloproteinases. Leukemia 10: 1520-1526.
Rosen PP, Oberman HA (1993) Tumors of the Mammary Gland. Washington DC.: AFIP.
Schnitt SJ, Abner A, Gelman R, Connolly JL, Recht A, Duda RB, Eberlein TJ, Mayzel K, Silver B, Harris JR (1994) The relationship between microscopic margins of resection and the risk of local recur-rence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 74: 1746-1751.
Scorilas A, Karameris A, Arnogiannaki N, Ardavanis A, Bassilopoulos P, Trangas T, Talieri M (2001) Overexpression of matrix-metalloproteinase-9 in human breast cancer: A potential favourable indicator in node-negative patients. Br J Cancer 84: 1488-1496.
Shekhar MP, Werdell J, Santner SJ, Pauley RJ, Tait L (2001) Breast stroma plays a dominant regulatory role in breast epithelial growth and. differentiation: Implications for tumor development and progression. Cancer Res 61: 1320-1326.
Singer CF, Kronsteiner N, Marton E, Kubista M, Cullen KJ, Hirtenlehner K, Seifert M, Kubista E (2002) MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions. Breast Cancer Res Treat 72: 69-77.
Soini Y, Hurskainen T, Hoyhtya M, Oikarinen A, Autio-Harmainen H (1994) 72 KD and 92 KD type IV collagenase, type IV collagen, and laminin mRNAs in breast cancer: A study by in situ hybridization. J Histochem Cytochem 42: 945-951.
Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, Werb Z (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98: 137-146.
Talvensaari-Mattila A, Paakko P, Hoyhtya M, Blanco-Sequeiros G, Turpeenniemi-Hujanen T (1998) Matrix metalloproteinase-2 immunoreactive protein: A marker of aggressiveness in breast car-cinoma. Cancer 83: 1153-1162.
Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T (1999) MMP-2 positivity and age less than 40 years increases the risk for recurrence in premenopausal patients with node-positive breast carcinoma. Breast Cancer Res Treat 58: 287-293.
Talvensaari-Mattila A, Paakko P, Blanco-Sequeiros G, Turpeenniemi-Hujanen T(2001) Matrix metalloproteinase-2 (MMP-2) is associated with the risk for a relapse in postmenopausal patients with node-positive breast carcinoma treated with antiestrogen adjuvant therapy. Breast Cancer Res Treat 65: 55-61.
Tavassoli FA(1999) Ductal intraepithelial neoplasia: Risk factors for sub-sequent development of invasive carcinoma. Pathology of the Breast. Stamford CT: Appleton & Lange, pp. 205-324.
Tlsty TD, Hein PW (2001) Know thy neighbor: Stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11: 54-59.
Tryggvason K, Hoyhtya M, Pyke C (1993) Type IV collagenases in invasive tumors. Breast Cancer Res Treat 24: 209-218.
Ueno H, Nakamura H, Inoue M, Imai K, Noguchi M, Sato H, Seiki M, Okada Y (1997) Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res 57: 2055-2060.
UICC (1997) TNM Classification of Malignant Tumours. New York: Wiley-Liss. Inc.
Visscher DW, Hoyhtya M, Ottosen SK, Liang CM, Sarkar FH, Crissman JD, Fridman R (1994) Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast car-cinomas correlates with tumor recurrence. Int J Cancer 59: 339-344.
Wiedorn KH, Goldmann T, Henne C, Kuhl H, Vollmer E (2001) EnVision +, a new dextran polymer-based signal enhancement tech-nique for in situ hybridization (ISH). J Histochem Cytochem 49: 1067-1071.
Yu M, Sato H, Seiki M, Thompson EW (1995) Complex regulation of membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation by concanavalin A in MDA-MB-231 human breast cancer cells. Cancer Res 55: 3272-3277.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lebeau, A., Müller-Aufdemkamp, C., Allmacher, C. et al. Cellular Protein and mRNA Expression Patterns of Matrix Metalloproteinases-2, -3 and -9 in Human Breast Cancer: Correlation with Tumour Growth. Histochem J 35, 443–455 (2004). https://doi.org/10.1023/B:HIJO.0000045943.26251.24
Issue Date:
DOI: https://doi.org/10.1023/B:HIJO.0000045943.26251.24