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Breast Cancer Research
Published in: Breast Cancer Research 5/2006

Open Access 01-10-2006 | Research article

Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: Relation to tumor phenotype and clinical outcome

Authors: Eleni Mylona, Christina Magkou, Ioanna Giannopoulou, George Agrogiannis, Sofia Markaki, Antonios Keramopoulos, Lydia Nakopoulou

Published in: Breast Cancer Research | Issue 5/2006

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Abstract

Introduction

Our aim was to study the expression pattern of tissue inhibitor of metalloproteinases (TIMP)-3 protein in invasive breast carcinoma, and its clinicopathological and prognostic value as well as its relation to markers indicative of the tumor phenotype.

Methods

Immunohistochemistry was performed on paraffin-embedded tissue specimens from 173 invasive breast carcinomas to detect the proteins TIMP-3, estrogen receptor (ER), progesterone receptor, p53, c-erbB-2, topoisomerase IIα and Bcl-2.

Results

TIMP-3 protein was immunodetected in the cytoplasm of the malignant cells and the peritumoral stroma, as well as in in situ carcinoma and normal epithelium. Reduced expression of TIMP-3 protein within cancer cells was correlated with carcinomas of high nuclear and histological grade (p = 0.032 and p = 0.015, respectively), and low ER expression (p = 0.053). Moreover, TIMP-3 immunopositivity was inversely correlated with the expression of p53 and topoIIα proteins (p = 0.002 and p = 0.008, respectively), whereas it was positively associated with Bcl-2 expression (p = 0.020). Reduced expression of TIMP-3 protein within cancer cells was found to have an unfavorable impact on disease-free survival (p = 0.052) in the entirety of the patient population, as well as in both subgroups of lymph-node-positive and mutant-p53-negative patients (p = 0.007 and p = 0.037, respectively). Stromal localization of TIMP-3 protein was found to have no clinicopathological or prognostic value.

Conclusion

This is the first immunohistochemical study to show that TIMP-3 protein within cancer cells is associated with tumor phenotype. Reduced expression of TIMP-3 protein within cancer cells was found to correlate with an aggressive tumor phenotype, negatively affecting the disease-free survival of both subgroups of lymph node-positive and mutant-p53-negative patients.
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Literature
1.
Freije J, Balbin M, Pendas AM, Sanchez LM, Puente XS, Lopez-Otin C: Matrix metalloproteinases and tumor progression. Adv Exp Med Biol. 2003, 532: 91-107.CrossRefPubMed
2.
Fassina G, Ferrari N, Brigati C, Benelli R, Santi L, Noonan DM, Albini A: Tissue inhibitors of metalloproteases: regulation and biological activities. Clin Exp Metastasis. 2000, 18: 111-120. 10.1023/A:1006797522521.CrossRefPubMed
3.
Jiang Y, Goldberg ID, Shi YE: Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene. 2002, 21: 2245-2252. 10.1038/sj.onc.1205291.CrossRefPubMed
4.
Yu WH, Yu S, Meng Q, Brew K, Woessner JF: TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem. 2000, 275: 31226-31232.CrossRefPubMed
5.
Wick M, Bürger C, Brüsselbach S, Lucibello C, Müller R: A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation and senescence. J Biol Chem. 1994, 269: 18953-18960.PubMed
6.
Loging WT, Reisman D: Inhibition of the putative tumor suppressor gene TIMP-3 by tumor-derived p53 mutants and wild type p53. Oncogene. 1999, 18: 7608-7615. 10.1038/sj.onc.1203135.CrossRefPubMed
7.
Baker AH, Zaltsman AB, George SJ, Newby AC: Divergent effects of tissue inhibitor of metalloproteinase-1, -2 or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation and death in vitro. J Clin Invest. 1998, 101: 1478-1487.CrossRefPubMedPubMedCentral
8.
Ahonen M, Baker AH, Kahari VM: Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res. 1998, 58: 2310-2315.PubMed
9.
Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC: Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer. 1999, 79: 1347-1355. 10.1038/sj.bjc.6690217.CrossRefPubMedPubMedCentral
10.
Yang TT, Hawkes SP: Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc Natl Acad Sci USA. 1992, 89: 10676-10680. 10.1073/pnas.89.22.10676.CrossRefPubMedPubMedCentral
11.
Bian J, Wang Y, Smith MR, Kim H, Jacobs C, Jackman J, Kung HF, Colburn NH, Sun Y: Characterization of a putative p53 binding site in the promoter of the mouse inhibitor of metalloproteinases-3 (TIMP-3) gene: TIMP-3 is not a p53 target gene. Carcinogenesis. 1996, 17: 1805-1811.CrossRefPubMed
12.
Bond M, Murphy G, Bennett MR, Newby AC, Baker AH: Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway. J Biol Chem. 2002, 277: 13787-13795. 10.1074/jbc.M111507200.CrossRefPubMed
13.
Smith MR, Kung H, Durum SK, Colburn NH, Sun Y: TIMP-3 induces cell death by stabilizing TNF-α receptors on the surface of human colon carcinoma cells. Cytokine. 1997, 9: 770-780. 10.1006/cyto.1997.0233.CrossRefPubMed
14.
Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR, Wakeham A, Mak TW, Khokha R: Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest. 2001, 108: 817-829. 10.1172/JCI200112067.CrossRefPubMedPubMedCentral
15.
Ahonen M, Ala-Aho R, Baker AH, George SI, Gernman R, Saarialho-Kere U, Kahari VM: Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. Mol Ther. 2002, 5: 705-715. 10.1006/mthe.2002.0606.CrossRefPubMed
16.
Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK, Baylin SB, Graff JR: Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain and other human cancers. Cancer Res. 1999, 59: 798-802.PubMed
17.
Darnton SJ, Hardie LJ, Muc RS, Wild CP, Casson AG: Tissue inhibitor of metalloproteinase-3 (TIMP-3) gene is methylated in the development of esophageal adenocarcinoma: loss of expression correlates with poor prognosis. Int J Cancer. 2005, 115: 351-358. 10.1002/ijc.20830.CrossRefPubMed
18.
Miyazaki T, Kato H, Nakajima M, Faried A, Takita J, Sohda M, Fukai Y, Yamaguchi S, Masuda N, Manda R, et al: An immunohistochemical study of TIMP-3 expression in oesophageal squamous cell carcinoma. Br J Cancer. 2004, 91: 1556-1560.PubMedPubMedCentral
19.
Curran S, Dundas SR, Buxton J, Leeman MF, Ramsay R, Murray IG: Matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers. Clin Cancer Res. 2004, 10: 8229-8234. 10.1158/1078-0432.CCR-04-0424.CrossRefPubMed
20.
Tunuguntla R, Ripley D, Sang QX, Chegini N: Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer. Gynecol Oncol. 2003, 89: 453-459. 10.1016/S0090-8258(03)00077-5.CrossRefPubMed
21.
Karan D, Lin FC, Bryan M, Ringel J, Moniaux N, Lin MF, Batra SK: Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinoma. Int J Oncol. 2003, 23: 1365-1371.PubMed
22.
Byrne JA, Tomasetto C, Rouyer N, Bellocq JP, Rio MC, Basset P: The tissue inhibitor of metalloproteinases-3 gene in breast carcinoma: identification of multiple polyadenylation sites and stromal pattern of expression. Mol Med. 1995, 1: 418-427.PubMedPubMedCentral
23.
Span PN, Lindberg R, Manders P, Tjan-Heijnen VC, Heuvel JJ, Beex LV, Sweep CG: Tissue inhibitor of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success. J Pathol. 2004, 202: 395-402. 10.1002/path.1528.CrossRefPubMed
24.
Kotzsch M, Farthmann J, Meye A, Fuessel S, Baretton G, Tjan-Heijnen VC, Schmitt M, Luther T, Sweep FC, Magdolen V, et al: Prognostic relevance of uPAR-del4/5 and TIMP-3 mRNA expression levels in breast cancer. Eur J Cancer. 2005, 41: 2760-2768. 10.1016/j.ejca.2005.09.002.CrossRefPubMed
25.
Tavassoéli FA, Devilee P: Pathology and Genetics: Tumors of the Breast and Female Genital Organs. 2003, Lyon: WHO Press, IARC WHO Classification of Tumours, No. 4.
26.
Robins P, Pinder S, de Klerk N: Histological grading of breast carcinomas: a study of interobserver agreement. Human Pathol. 1995, 6: 873-879. 10.1016/0046-8177(95)90010-1.CrossRef
27.
Union International Contre Cancer: TNM Classification of International Union against Cancer. TNM Atlas, 3rd revision. Edited by: Hermanek P, Sabin H. 1992, Berlin: Springer-Verlag, 15-25. 4
28.
Laskawi NH, Wahlers A, Hemmerlein B: Expression of matrix metalloproteinases MMP-2, MMP-9 and tissue inhibitors TIMP-1, -2, and -3 in benign and malignant tumours of the salivary gland. Histopathology. 2004, 44: 222-231. 10.1111/j.0309-0167.2004.01814.x.CrossRefPubMed
29.
McCleilland RA, Wilson D, Leake R, Finlay P, Nicholson RI: A multicentre study into the reliability of steroid receptor immunocytochemical assay quantification. Eur J Cancer. 1991, 27: 711-716.CrossRef
30.
Nakopoulou L, Lazaris AC, Kavantzas N, Alexandrou P, Athanassiadou P, Keramopoulos A, Davaris P: DNA topoisomerase II-α immunoreactivity as a marker of tumor aggressiveness in invasive breast cancer. Pathobiology. 2000, 68: 137-143. 10.1159/000055914.CrossRefPubMed
31.
Nakopoulou L, Stefanaki K, Panayotopoulou E, Giannopoulou I, Athanassiadou P, Gakiopoulou-Givalou H, Louvrou A: Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. Hum Pathol. 2002, 33: 863-870. 10.1053/hupa.2002.126879.CrossRefPubMed
32.
Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature. 2000, 408: 307-310. 10.1038/35042675.CrossRefPubMed
33.
Vousden KH, Prives C: p53 and prognosis: new insights and further complexity. Cell. 2005, 120: 7-10.PubMed
34.
Lynch BJ, Guinee DG, Holden JA: Human DNA topoisomerase II-α: a new marker of cell proliferation in invasive breast cancer. Hum Pathol. 1997, 28: 1180-1188. 10.1016/S0046-8177(97)90256-2.CrossRefPubMed
35.
Adams JM, Cory S: Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci. 2001, 26: 61-66. 10.1016/S0968-0004(00)01740-0.CrossRefPubMed
36.
Nothnick WB, Zhang X, Zhou HE: Steroidal regulation of uterine edema and tissue inhibitors of metalloproteinase (TIMP)-3 messenger RNA expression is altered in TIMP-1 deficient mice. Biol Reprod. 2004, 70: 500-508. 10.1095/biolreprod.103.020834.CrossRefPubMed
37.
Fata JE, Chaudhary V, Khokha R: Cellular turnover in the mammary gland is corrected with systemic levels of progesterone and not 17β-estradiol during the estrous cycle. Biol Reprod. 2001, 65: 680-688. 10.1095/biolreprod65.3.680.CrossRefPubMed
Metadata
Title
Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: Relation to tumor phenotype and clinical outcome
Authors
Eleni Mylona
Christina Magkou
Ioanna Giannopoulou
George Agrogiannis
Sofia Markaki
Antonios Keramopoulos
Lydia Nakopoulou
Publication date
01-10-2006
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2006
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1607

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