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

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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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      Most cited references 39

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      Surfing the p53 network.

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        Life-or-death decisions by the Bcl-2 protein family.

         Jenny Cory,  J. Adams (2000)
        In response to intracellular damage and certain physiological cues, cells enter the suicide program termed apoptosis, executed by proteases called caspases. Commitment to apoptosis is typically governed by opposing factions of the Bcl-2 family of cytoplasmic proteins. Initiation of the proteolytic cascade requires assembly of certain caspase precursors on a scaffold protein, and the Bcl-2 family determines whether this complex can form. Its pro-survival members can act by sequestering the scaffold protein and/or by preventing the release of apoptogenic molecules from organelles such as mitochondria. Pro-apoptotic family members act as sentinels for cellular damage: cytotoxic signals induce their translocation to the organelles where they bind to their pro-survival relatives, promote organelle damage and trigger apoptosis.
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          Complex roles of tissue inhibitors of metalloproteinases in cancer.

          Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These effects may be through MMP-dependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory effect and stimulatory effect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identified as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.
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            Author and article information

            Affiliations
            [1]Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, GR-115 27 Athens, Greece
            [2]Department of Pathology, Attikon Hospital, 1 Rimini Street, GR-124 62 Chaidari, Athens, Greece
            [3]Department of Pathology, Alexandra Hospital, 80 Vasilissis Sofias Street, GR-115 28 Athens, Greece
            Contributors
            Journal
            Breast Cancer Res
            Breast Cancer Research
            BioMed Central (London)
            1465-5411
            1465-542X
            2006
            10 October 2006
            : 8
            : 5
            : R57
            1779495
            bcr1607
            17032447
            10.1186/bcr1607
            Copyright © 2006 Mylona et al.; licensee BioMed Central Ltd.

            This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Categories
            Research Article

            Oncology & Radiotherapy

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