Top

Published in:

Open Access 01-12-2008 | Research article

Plasma MMP1 and MMP8 expression in breast cancer: Protective role of MMP8 against lymph node metastasis

Authors: Julie Decock, Wouter Hendrickx, Ulla Vanleeuw, Vanya Van Belle, Sabine Van Huffel, Marie-Rose Christiaens, Shu Ye, Robert Paridaens

Published in: BMC Cancer | Issue 1/2008

Abstract

Background

Elevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer.

Methods

A total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics.

Results

Median plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis.

Conclusion

In summary, we observed differences in MMP1 and MMP8 plasma levels between healthy controls and breast cancer patients as well as between breast cancer patients. Interestingly, our results suggest that MMP8 may affect the metastatic behaviour of breast cancer cells through protection against lymph node metastasis, underlining the importance of anti-target identification in drug development.

Available only for authorised users

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P: Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007, 18: 581-592. 10.1093/annonc/mdl498.CrossRefPubMed

Weigelt B, Wessels LF, Bosma AJ, Glas AM, Nuyten DS, He YD, Dai H, Peterse JL, van't Veer LJ: No common denominator for breast cancer lymph node metastasis. Br J Cancer. 2005, 93: 924-932. 10.1038/sj.bjc.6602794.CrossRefPubMedPubMedCentral

Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002, 2: 161-174. 10.1038/nrc745.CrossRefPubMed

Deryugina EI, Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006, 25: 9-34. 10.1007/s10555-006-7886-9.CrossRefPubMed

Coskun U, Yamac D, Gulbahar O, Sancak B, Karaman N, Ozkan S: Locally advanced breast carcinoma treated with neoadjuvant chemotherapy: are the changes in serum levels of YKL-40, MMP-2 and MMP-9 correlated with tumor response?. Neoplasma. 2007, 54: 348-352.PubMed

Farias E, Ranuncolo S, Cresta C, Specterman S, Armanasco E, Varela M, Lastiri J, Pallotta MG, Bal De Kier JE, Puricelli L: Plasma metalloproteinase activity is enhanced in the euglobulin fraction of breast and lung cancer patients. Int J Cancer. 2000, 89: 389-394. 10.1002/1097-0215(20000720)89:4<389::AID-IJC12>3.0.CO;2-J.CrossRefPubMed

La Rocca G, Pucci-Minafra I, Marrazzo A, Taormina P, Minafra S: Zymographic detection and clinical correlations of MMP-2 and MMP-9 in breast cancer sera. Br J Cancer. 2004, 90: 1414-1421. 10.1038/sj.bjc.6601725.CrossRefPubMed

Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I: A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma. Clin Cancer Res. 2004, 10: 1057-1063. 10.1158/1078-0432.CCR-03-0047.CrossRefPubMed

Liu SC, Yang SF, Yeh KT, Yeh CM, Chiou HL, Lee CY, Chou MC, Hsieh YS: Relationships between the level of matrix metalloproteinase-2 and tumor size of breast cancer. Clin Chim Acta. 2006, 371: 92-96. 10.1016/j.cca.2006.02.026.CrossRefPubMed

10.

Quaranta M, Daniele A, Coviello M, Venneri MT, Abbate I, Caringella ME, Di TS, Divella R, Trerotoli P, Di GM, Schittulli F, Fransvea E, Giannelli G: MMP-2, MMP-9, VEGF and CA 15.3 in breast cancer. Anticancer Res. 2007, 27: 3593-3600.PubMed

11.

Ranuncolo SM, Armanasco E, Cresta C, Bal De Kier JE, Puricelli L: Plasma MMP-9 (92 kDa-MMP) activity is useful in the follow-up and in the assessment of prognosis in breast cancer patients. Int J Cancer. 2003, 106: 745-751. 10.1002/ijc.11288.CrossRefPubMed

12.

Sheen-Chen SM, Chen HS, Eng HL, Sheen CC, Chen WJ: Serum levels of matrix metalloproteinase 2 in patients with breast cancer. Cancer Lett. 2001, 173: 79-82. 10.1016/S0304-3835(01)00657-7.CrossRefPubMed

13.

Talvensaari-Mattila A, Turpeenniemi-Hujanen T: Preoperative serum MMP-9 immunoreactive protein is a prognostic indicator for relapse-free survival in breast carcinoma. Cancer Lett. 2005, 217: 237-242. 10.1016/j.canlet.2004.06.056.CrossRefPubMed

14.

Zucker S, Lysik RM, Zarrabi MH, Moll U: M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res. 1993, 53: 140-146.PubMed

15.

Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, Boyd D, Nicolson G, Montana S: Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci. 1999, 878: 212-227. 10.1111/j.1749-6632.1999.tb07687.x.CrossRefPubMed

16.

Ala-aho R, Kahari VM: Collagenases in cancer. Biochimie. 2005, 87: 273-286. 10.1016/j.biochi.2004.12.009.CrossRefPubMed

17.

Rodriguez FO, Fernandez Gomez JM, Palou RJ, Escaf BS, Vizoso F, Villavicencio MH: Significance of collagenase 3 (matrix metalloproteinase 13) in invasive bladder cancer: correlation with pathological parameters. Urol Int. 2007, 78: 140-144. 10.1159/000098072.CrossRef

18.

Van Lint P, Libert C: Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 2006, 17: 217-223. 10.1016/j.cytogfr.2006.04.001.CrossRefPubMed

19.

Mannello F, Tonti GA: Gelatinase concentrations and zymographic profiles in human breast cancer: matrix metalloproteinases circulating in plasma are better markers for the subclassification and early prediction of cancer: the coagulation/fibrinolysis pathways alter the release, activation and recovery of different gelatinases in serum. Int J Cancer. 2007, 121: 216-218. 10.1002/ijc.22652.CrossRefPubMed

20.

Gonzalez-Angulo AM, Hennessy BT, Broglio K, Meric-Bernstam F, Cristofanilli M, Giordano SH, Buchholz TA, Sahin A, Singletary SE, Buzdar AU, Hortobagyi GN: Trends for inflammatory breast cancer: is survival improving?. Oncologist. 2007, 12: 904-912. 10.1634/theoncologist.12-8-904.CrossRefPubMed

21.

Fowlkes JL, Enghild JJ, Suzuki K, Nagase H: Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. J Biol Chem. 1994, 269: 25742-25746.PubMed

22.

Agarwal D, Goodison S, Nicholson B, Tarin D, Urquidi V: Expression of matrix metalloproteinase 8 (MMP-8) and tyrosinase-related protein-1 (TYRP-1) correlates with the absence of metastasis in an isogenic human breast cancer model. Differentiation. 2003, 71: 114-125. 10.1046/j.1432-0436.2003.710202.x.CrossRefPubMed

23.

Balbin M, Fueyo A, Tester AM, Pendas AM, Pitiot AS, Astudillo A, Overall CM, Shapiro SD, Lopez-Otin C: Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet. 2003, 35: 252-257. 10.1038/ng1249.CrossRefPubMed

24.

Montel V, Kleeman J, Agarwal D, Spinella D, Kawai K, Tarin D: Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression. Cancer Res. 2004, 64: 1687-1694. 10.1158/0008-5472.CAN-03-2047.CrossRefPubMed

25.

Decock J, Long JR, Laxton RC, Shu XO, Hodgkinson C, Hendrickx W, Pearce EG, Gao YT, Pereira AC, Paridaens R, Zheng W, Ye S: Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis. Cancer Res. 2007, 67: 10214-10221. 10.1158/0008-5472.CAN-07-1683.CrossRefPubMed

26.

Moilanen M, Pirila E, Grenman R, Sorsa T, Salo T: Expression and regulation of collagenase-2 (MMP-8) in head and neck squamous cell carcinomas. J Pathol. 2002, 197: 72-81. 10.1002/path.1078.CrossRefPubMed

27.

Stadlmann S, Pollheimer J, Moser PL, Raggi A, Amberger A, Margreiter R, Offner FA, Mikuz G, Dirnhofer S, Moch H: Cytokine-regulated expression of collagenase-2 (MMP-8) is involved in the progression of ovarian cancer. Eur J Cancer. 2003, 39: 2499-2505. 10.1016/j.ejca.2003.08.011.CrossRefPubMed

28.

Stenman M, Paju A, Hanemaaijer R, Tervahartiala T, Leminen A, Stenman UH, Konttinen YT, Sorsa T: Collagenases (MMP-1, -8 and -13) and trypsinogen-2 in fluid from benign and malignant ovarian cysts. Tumour Biol. 2003, 24: 9-12. 10.1159/000070655.CrossRefPubMed

29.

Overall CM, Kleifeld O: Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006, 6: 227-239. 10.1038/nrc1821.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/8/77/prepub

Title: Plasma MMP1 and MMP8 expression in breast cancer: Protective role of MMP8 against lymph node metastasis
Authors: Julie Decock
Wouter Hendrickx
Ulla Vanleeuw
Vanya Van Belle
Sabine Van Huffel
Marie-Rose Christiaens
Shu Ye
Robert Paridaens
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-8-77

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2008

Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability

Municipal distribution of ovarian cancer mortality in Spain

A haplotype of polymorphisms in ASE-1, RAI and ERCC1and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a danish prospective case-cohort study

Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

Metastatic susceptibility locus, an 8p hot-spot for tumour progression disrupted in colorectal liver metastases: 13 candidate genes examined at the DNA, mRNA and protein level

Estrogen receptor alpha gene polymorphism and endometrial cancer risk – a case-control study

Keynote webinar | Spotlight on antibody–drug conjugates in cancer