Clinical significance of cathepsin D concentration in tumor cytosol of primary breast cancer

Rodrguez, J.; V�zquez, Julio; Corte,; Lamelas, Marı́a L.; Bongera, Miguel; Corte, M.G.; Alvarez, A. M.; Allende, M.T.; González, Lucía; Snchez, M.; Vijande, M.; Garca-Muiz, J.L.

doi:10.5301/jbm.2008.679

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…In total, 19 evaluable studies [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] for OS (7809 patients) and 15 evaluable studies 28,31,33,35,[39][40][41][43][44][45][46][47][48][49][50] for DFS (7546 patients) were included. Subgroup analysis for OS was possible using five studies with 784 node-positive patients, 27,28,36,43,51 five studies with 1193 node-negative patients, 28,30,34,35,43 and four studies with 575 adjuvant chemotherapy-treated patients. 34,36,40,51 Subgroup analysis for DFS was possible for six studies with 2633 node-positive patients,…”

Section: Study Characteristicsmentioning

confidence: 99%

Prognostic role of high cathepsin D expression in breast cancer: a systematic review and meta-analysis

Kang

Jeong

et al. 2020

Ther Adv Med Oncol

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Background: High cathepsin D has been associated with poor prognosis in breast cancer; however, the results of many studies are controversial. Here, we assessed the association between high cathepsin D levels and worse breast cancer prognosis by conducting a meta-analysis. Methods: A comprehensive search strategy was used to search relevant literature in PUBMED and EMBASE by September 2018. The meta-analysis was performed in Review Manager 5.3 using hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 15,355 breast cancer patients from 26 eligible studies were included in this meta-analysis. Significant associations between elevated high cathepsin D and poor overall survival (OS) (HR = 1.61, 95% CI: 1.35–1.92, p < 0.0001) and disease-free survival (DFS) (HR = 1.52, 95% CI: 1.31–2.18, p < 0.001) were observed. In the subgroup analysis for DFS, high cathepsin D was significantly associated with poor prognosis in node-positive patients (HR = 1.38, 95% CI: 1.25–1.71, p < 0.00001), node-negative patients (HR = 1.78, 95% CI: 1.39–2.27, p < 0.0001), early stage patients (HR = 1.73, 95% CI: 1.34–2.23, p < 0.0001), and treated with chemotherapy patients (HR = 1.60, 95% CI: 1.21–2.12, p < 0.001). Interestingly, patients treated with tamoxifen had a low risk of relapse when their cathepsin D levels were high (HR = 0.71, 95% CI: 0.52–0.98, p = 0.04) and a high risk of relapse when their cathepsin D levels were low (HR = 1.50, 95% CI: 1.22–1.85, p = 0.0001). Conclusions: Our meta-analysis suggests that high expression levels of cathepsin D are associated with a poor prognosis in breast cancer. Based on our subgroup analysis, we believe that cathepsin D can act as a marker for poor breast cancer prognosis and also as a therapeutic target for breast cancer.

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Section: Study Characteristicsmentioning

confidence: 99%

Prognostic role of high cathepsin D expression in breast cancer: a systematic review and meta-analysis

Kang

Jeong

et al. 2020

Ther Adv Med Oncol

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“…The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (Westley and May, 1999;Rodriguez et al, 2005), is overexpressed and secreted at high levels by human epithelial breast cancer cells (Vashishta et al, 2009;Nicotra et al, 2010;Radiskt et al, 2010;Masson et al, 2011). Cath-D stimulates cancer cell proliferation, fibroblast outgrowth, angiogenesis and metastasis (Vashishta et al, 2007;Hu et al, 2008;Ohri et al, 2008).…”

Section: Aspartate Proteasesmentioning

confidence: 99%

Role of proteases in cancer: A review

Rakash¹

2012

Biotechnol. Mol. Biol. Rev.

101

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Proteases in normal cells are important in carrying out biological processes. In living systems, a balance between proteases and their anti-proteases occur, and disturbance of balance leads to many diseases like cancer. Steps starting from tumor initiation, growth, metastasis and finally invasion into some other site involve all five classes of proteases: serine, cysteine, aspartate, threonine and matrix metalloproteases. The activity of set of peptides in cancer progression is known as cancer 'degradome'. A great number of reports have shown a correlation between the activity of lysosomal cysteine proteases and tumor progression. Trypsin, one of the typical well-known digestive serine protease has also been found to be involved in various cancers and promotes proliferation, invasion and metastasis. The colorectal cancer with trypsin expression has poor prognosis and shorter disease free survival. Protease involvement in cancer suggests the use of protease inhibitors as anticancer drugs. In this review, we will focus on role of proteases in various processes of carcinogenesis and some protease inhibitor based drugs.

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“…However, cathepsin-B and cathepsin-D have been reported to be hyper-secreted in cancer [Koblinski et al, 2002;Mohamed and Sloane, 2006]. Over three decades, various studies have associated cathepsin-D with breast cancer [Greco et al, 2000;Harbeck et al, 2000;Gaci et al, 2001;Bossard et al, 2003;Kute et al, 2004;Anim et al, 2005;Rodriguez et al, 2005;Cheng et al, 2008;Vasudev et al, 2009] and other degenerative diseases [Rochefort, 1990]. However, the molecular mechanism by which cathepsin-D affects cancer progression remains largely unknown.…”

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confidence: 99%

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

Arodola

Soliman

2016

J of Cellular Biochemistry

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The flap region in aspartic proteases is a unique structural feature to this class of enzymes, and found to have a profound impact on protein overall structure, function, and dynamics. Understanding the structure and dynamic behavior of the flap regions is crucial in the design of selective inhibitors against aspartic proteases. Cathepsin-D, an aspartic protease enzyme, has been implicated in a long list of degenerative diseases as well as breast cancer progression. Presented herein, for the first time, is a comprehensive description of the conformational flap dynamics of cathepsin-D using a comparative 50 ns "multiple" molecular dynamics simulations. Diverse collective metrics were proposed to accurately define flap dynamics. These are distance d1 between the flap tips residues (Gly79 and Met301); dihedral angle ϕ; in addition to TriCα angles Gly79-Asp33-Asp223, θ1 , and Gly79-Asp223-Met301, θ2 . The maximum distance attained throughout the simulation was 17.42 and 11.47 Å for apo and bound cathepsin-D, respectively, while the minimum distance observed was 8.75 and 6.32 Å for apo and bound cathepsin-D, respectively. The movement of the flap as well as the twist of the active pocket can properly be explained by measuring the angle, θ1 , between Gly79-Asp33-Met301 and correlating it with the distance Cα of the flap tip residues. The asymmetrical opening of the binding cavity was best described by the large shift of -6.26° to +20.94° in the dihedral angle, ϕ, corresponding to the full opening of the flap at a range of 31-33 ns. A wide-range of post-dynamic analyses was also applied in this report to supplement our findings. We believe that this report would augment current efforts in designing potent structure-based inhibitors against cathepsin-D in the treatment of breast cancer and other degenerative diseases. J. Cell. Biochem. 117: 2643-2657, 2016. © 2016 Wiley Periodicals, Inc.

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Clinical significance of cathepsin D concentration in tumor cytosol of primary breast cancer

Abstract: This study suggests that elevated intratumoral cathepsin D levels may identify a subset of node-positive breast cancer patients showing a high probability of earlier death. (Int J Biol Markers 2005; 20: 103-11).

Cited by 14 publications

References 30 publications

Prognostic role of high cathepsin D expression in breast cancer: a systematic review and meta-analysis

Prognostic role of high cathepsin D expression in breast cancer: a systematic review and meta-analysis

Role of proteases in cancer: A review

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

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