Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Klintman, Marie; Würtz, Sidse Ørnbjerg; Christensen, Ib Jarle; Hertel, P. B.; Fernö, Mårten; Malmberg, Martin; Mouridsen, Henning T.; Cold, Frederik; Schrohl, Anne-Sofie; Foekens, John A.; Malmström, Per Uno; Brünner, Nils

doi:10.1007/s10549-009-0483-1

Cited by 15 publications

(10 citation statements)

References 22 publications

(47 reference statements)

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“…Although MMP expression generally has been associated with tumor progression in several cancer forms including breast cancer (36), clinical trials with broad-spectrum MMP inhibitors have failed, and in some cases, patients treated with the inhibitors even showed significantly poorer survival than patients receiving placebo (3). These results are further supported by recent data showing unfavorable effects of TIMP-1 in breast cancer patients (14)(15)(16). Moreover, recent data, including MMP-9 knockout mice, has clearly shown MMP-9 may be involved in tumor regression (5).…”

Section: Discussionsupporting

confidence: 76%

“…Similar to MMPs, the role of TIMPs in cancer is reported contradictory and both tumor-protective and tumor-enhancing properties have been reported (10)(11)(12)(13). In breast cancer patients, high tumor and serum levels of TIMP-1 have been associated with decreased response to chemotherapy and decreased survival, suggesting a detrimental effect of TIMP-1 (14)(15)(16).…”

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confidence: 99%

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Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Leifler

Svensson

Abrahamsson

et al. 2013

The Journal of Immunology

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Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro- and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell–derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities.

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Leifler

Svensson

Abrahamsson

et al. 2013

The Journal of Immunology

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“…Among MMPs and TIMPs, TIMP-1 is frequently overexpressed and shown to serve as a prognostic marker in several types of human cancers including breast cancer, prostate cancer, lung cancer, melanoma, multiple myeloma, and glioblastoma [13], [14], [15], [16], [17], [18], [19], [20], [21]. This seemed at first counter-intuitive considering its prominent role in MMP inhibition, thereby suppressing matrix degradation necessary for tumor cell invasion.…”

Section: Introductionmentioning

confidence: 99%

TIMP-1 Induces an EMT-Like Phenotypic Conversion in MDCK Cells Independent of Its MMP-Inhibitory Domain

et al. 2012

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Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) regulate epithelial-mesenchymal transition (EMT) critical for the development of epithelial organs as well as cancer cell invasion. TIMP-1 is frequently overexpressed in several types of human cancers and serves as a prognostic marker. The present study investigates the roles of TIMP-1 on the EMT process and formation of the lumen-like structure in a 3D Matrigel culture of MDCK cells. We show that TIMP-1 overexpression effectively prevents cell polarization and acinar-like structure formation. TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG, TWIST, ZEB1 and ZEB2, leading to downregulation of epithelial marker and upregulation of mesenchymal markers. Importantly, TIMP-1′s ability to induce the EMT-like process is independent of its MMP-inhibitory domain. To our surprise, TIMP-1 induces migratory and invasive properties in MDCK cells. Here, we present a novel finding that TIMP-1 signaling upregulates MT1-MMP and MMP-2 expression, and potentiates MT1-MMP activation of pro-MMP-2, contributing to tumor cell invasion. In spite of the fact that TIMP-1, as opposed to TIMP-2, does not interact with and inhibit MT1-MMP, TIMP-1 may act as a key regulator of MT1-MMP/MMP-2 axis. Collectively, our findings suggest a model in which TIMP-1 functions as a signaling molecule and also as an endogenous inhibitor of MMPs. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression.

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“…In the exploratory study by Schrohl et al [36] results suggested that patients with high levels of TIMP-1 are less responsive to chemotherapy, but the study did not include an analysis of OS. On the other hand, the second study by Klintman et al [35] which supports the association of TIMP-1 with objective response to chemotherapy, did not find TIMP-1 to be associated with either progression free survival (PFS) or OS. The results presented in this manuscript suggest that TIMP-1 protein expression in cancer cells in the primary tumor evaluated by IHC is associated with improved OS for advanced breast cancer patients receiving D or GD.…”

Section: Discussionmentioning

confidence: 97%

“…The majority of breast cancer studies on TIMP-1 and association with prognosis and response to chemotherapy have focused on patients receiving adjuvant chemotherapy [2,8,18,20,34], whereas only two studies have included patients with advanced breast cancer [35,36]. These two studies both measured TIMP-1 levels in the primary tumors using an enzyme-linked immunosorbent assay-based approach and included patients receiving cyclophosphamide/methotrexate/5-fluorouracil or anthracycline-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group

et al. 2014

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BackgroundTissue inhibitor of metalloproteinases-1 (TIMP-1) has anti-apoptotic functions, which may protect TIMP-1 positive cancer cells from the effects of chemotherapy such as docetaxel and gemcitabine. The purpose of the present study was to evaluate TIMP-1 immunoreactivity as a prognostic and predictive marker in advanced breast cancer patients receiving docetaxel (D) or gemcitabine plus docetaxel (GD).MethodsPatients with locally advanced or metastatic breast cancer who were assigned to D or GD by participation in a randomized phase III trial were included in the study. Assessment of TIMP-1 status was performed retrospectively on primary tumor whole-tissue sections by immunohistochemistry and tumor samples were considered positive if epithelial breast cancer cells were stained by the anti-TIMP-1 monoclonal antibody VT7. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between TIMP-1 status and outcome after chemotherapy were analyzed by Kaplan-Meier estimates and Cox proportional hazards regression models.ResultsTIMP-1 status was available from 264 of 337 patients and 210 (80%) of the tumors were classified as cancer cell TIMP-1 positive. No significant difference for TTP between TIMP-1 positive versus TIMP-1 negative patients was observed in multivariate analysis, and RR did not differ according to TIMP-1 status. However, patients with TIMP-1 positive tumors had a significant reduction in OS events (hazard ratio = 0.71, 95% confidence interval (CI) = 0.52-0.98, P = 0.03). Additionally, a borderline significant interaction for OS was observed between TIMP-1 status and benefit from GD compared to D (Pinteraction = 0.06) such that median OS increased by nine months for TIMP-1 negative patients receiving GD.ConclusionsTIMP-1 status was an independent prognostic factor for OS but not TTP in patients with advanced breast cancer receiving either D or GD. There was no statistically significant interaction between TIMP-1 status and treatment, but a trend towards an incremental OS from the addition of gemcitabine to docetaxel in patients with TIMP-1 negative tumors suggests further investigation.

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Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Cited by 15 publications

References 22 publications

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

TIMP-1 Induces an EMT-Like Phenotypic Conversion in MDCK Cells Independent of Its MMP-Inhibitory Domain

TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group

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