TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis

Davidsen, M L; Würtz, Sø; Rømer, Maria Unni; Sørensen, Nanna Møller; Johansen, Susanne; Christensen, I. J.; Larsen, Jørgen K.; Offenberg, Hanne; Brünner, Nils; Lademann, Ulrik

doi:10.1038/sj.bjc.6603378

Cited by 66 publications

(60 citation statements)

References 21 publications

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“…More recently, we have shown that TIMP-1 immunoreactivity in the cancer cells is significantly associated with benefit from adjuvant anthracycline treatment in patients with primary breast cancer [15]. These clinical findings have also been supported by in vitro cell studies [16,17]. For example, murine fibrosarcoma cells deficient of the TIMP-1 gene were shown to be considerably more sensitive to chemotherapy compared with their genetically identical wild-type controls [16].…”

Section: Introductionsupporting

confidence: 61%

“…These clinical findings have also been supported by in vitro cell studies [16,17]. For example, murine fibrosarcoma cells deficient of the TIMP-1 gene were shown to be considerably more sensitive to chemotherapy compared with their genetically identical wild-type controls [16]. Likewise, transfected MCF10A cells overexpressing TIMP-1 were less sensitive to adriamycin compared with non-transfected cells [17].…”

Section: Introductionsupporting

confidence: 54%

“…In this regard, TIMP-1 has been shown to inhibit apoptosis [16,17], and since chemotherapy works by inducing apoptosis in the cancer cells, we have raised the hypothesis that TIMP-1 protects cells expressing high levels of TIMP-1 against chemotherapy by inhibiting apoptosis. In support of this hypothesis, our laboratory has recently shown that murine fibrosarcoma cells deficient of the TIMP-1 gene were significantly more sensitive to chemotherapy-induced apoptosis compared to their wildtype controls [16]. These results have recently been extended to a human breast carcinoma cell system [24].…”

Section: Discussionmentioning

confidence: 99%

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

Klintman¹,

Würtz²,

Christensen³

et al. 2009

Breast Cancer Res Treat

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In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to firstline chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97-2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Klintman¹,

Würtz²,

Christensen³

et al. 2009

Breast Cancer Res Treat

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“…44,[73][74][75][76] Accordingly, we found that TIMP-1 deficiency, but not TIMP-2 deficiency, enhanced airway re-epithelialization implying that the regulation of matrilysin-mediated cell spreading and migration is specific to TIMP-1 and is not a generalized process among different members of the TIMP family. Although TIMP-1 can modulate cell apoptosis, survival, and proliferation through MMP-independent mechanisms, 25,77,78 we conclude that the moderating effect TIMP-1 confers on epithelial regeneration is a consequence of its ability to block MMP activity, specifically that of matrilysin. Indeed, the phenotype was reversed when a hydroxamate MMP inhibitor or matrilysin inhibitory antibody was added to wounded Timp1 Ϫ/Ϫ ALI cultures suggesting that TIMP-1 moderates re-epithelialization through MMP inhibition, specifically matrilysin.…”

Section: Discussionmentioning

confidence: 98%

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Chen

McGuire

Hackman

et al. 2008

The American Journal of Pathology

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Obliterative bronchiolitis (OB) is the histopathological finding in chronic lung allograft rejection. Mounting evidence suggests that epithelial damage drives the development of airway fibrosis in OB. Tissue inhibitor of metalloproteinase (TIMP)-1 expression increases in lung allografts and is associated with the onset of allograft rejection. Furthermore, in a mouse model of OB, airway obliteration is reduced in TIMP-1-deficient mice. Matrilysin (matrix metallproteinase-7) is essential for airway epithelial repair and is required for the re-epithelialization of airway wounds by facilitating cell migration; therefore, the goal of this study was to determine whether TIMP-1 inhibits re-epithelialization through matrilysin. We found that TIMP-1 and matrilysin co-localized in the epithelium of human lungs with OB and both co-localized and co-immunoprecipitated in wounded primary airway epithelial cultures. TIMP-1-deficient cultures migrated faster, and epithelial cells spread to a greater extent compared with wild-type cultures. TIMP-1 also inhibited matrilysin-mediated cell migration and spreading in vitro. In vivo, TIMP-1 deficiency enhanced airway re-epithelialization after naphthalene injury. Furthermore, TIMP-1 and matrilysin co-localized in airway epithelial cells adjacent to the wound edge. Our data demonstrate that TIMP-1 interacts with matrix metalloproteinases and regulates matrilysin activity during airway epithelial repair. Furthermore, we speculate that TIMP-1 overexpression restricts airway re-epithelialization by inhibiting matrilysin activity, contributing to a stereotypic injury response that promotes airway fibrosis via bronchiole airway epithelial damage and obliteration. Bronchiolitis obliterans syndrome (BOS) is the manifestation of chronic lung rejection and limits the 5-year survival after lung transplant to less than 50%.1 In comparison, transplantations of other solid organs, such as the heart, pancreas, liver, and kidneys, have 5-year survival rates exceeding 70%.2 Obliterative bronchiolitis (OB) is the histopathological equivalent of BOS and is characterized by small airway fibrosis that contributes to progressive respiratory failure and death.3 Although the pathogenesis of OB is poorly understood, evidence suggests that the primary immunological target in the lung allograft is the airway epithelium. 4 -7 Moreover, aberrant airway re-epithelialization is apparently sufficient for the progression of fibrosis during the allograft rejection process. -13The airway epithelium is an important barrier in the innate defenses of the lung.14 After lung transplantation, persistent allo-dependent (eg, acute rejection) and alloindependent (eg, infection, ischemia) pressures on the airway epithelium necessitate rapid re-epithelialization to prevent further damage that can contribute to inflammation and fibrosis.3 Disturbances in the epithelial barrier are quickly repaired through coordinated processes by which epithelial cells bordering the injury quickly spread over the denuded basement membrane. [15][...

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“…Recent studies have shown that elevated levels of TIMP-1 in plasma or serum may give rise to endocrine resistance in metastatic breast cancer (Lipton et al, 2008). In vitro and in vivo studies have also suggested that a high level of TIMP-1 protects tumour cells against chemotherapy-induced apoptosis (Davidsen et al, 2006;Schrohl et al, 2006). Data presented by Ejlertsen et al (2010) at SABCS (2008) suggested that TIMP-1 and TOP2A collectively predict response to anthracycline therapy.…”

Section: Other Potential or Emerging Markersmentioning

confidence: 99%

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

2010

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The search for a predictive marker of sensitivity to anthracycline-based chemotherapy has proven challenging. Despite human epidermal growth factor receptor 2 (HER2) being a strong prognostic marker in breast cancer, the only therapies with which there is a recognized functional link to the HER2 oncogene are those directly targeting the molecule itself. Despite this, HER2 has been extensively assessed as a predictive marker in a variety of chemotherapy regimens including anthracyclines. Analysis of anthracycline response in patients with HER2 amplification has given conflicting results. This led to the suggestion that HER2 amplification was acting as a surrogate for the gene encoding topoisomerase IIa (TOP2A), a direct cellular target of anthracyclines. Despite an attractive functional link between TOP2A and anthracyclines, published studies have failed to show strong evidence of an interaction between TOP2A genetic aberrations and anthracycline response. A number of other biomarkers have also been assessed for their role in predicting anthracycline response, including TP53 (tumour protein 53) and BRCA1 (breast cancer 1, early onset), together with an increasing emergence of gene expression profiling to produce predictive signatures of response. Moreover, recent evidence has emerged from presentations suggesting new candidate markers of response that warrant further investigation: Chr17CEP duplication and tissue inhibitor of metalloproteases 1. This review will discuss research into HER2 and TOP2A as predictive markers of anthracycline response and will focus on current research into other possible candidate predictive markers.

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TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis

Cited by 66 publications

References 21 publications

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

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

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

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