Prognostic significance of cathepsins B and L in primary human breast cancer.

Foekens, John A.; Kos, Janko; Peters, H. A.; Krašovec, Marta; Look, Maxime P.; Cimerman, Nina; Gelder, Marion E. Meijer–van; Henzen‐Logmans, S. C.; Putten, Wim L.J. van; Klijn, Jan G.M.

doi:10.1200/jco.1998.16.3.1013

Cited by 132 publications

(71 citation statements)

References 25 publications

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“…In our analysis, the transgenic expression of human CTSL in mouse mammary cancer led to an increase in lung metastatic burden in agreement with clinical studies that established positive correlations of CTSL with metastasis and poor prognosis in mammary cancer patients (6,7,9). It needs to be further explored at which stage of tumor progression high CTSL levels are especially critical.…”

Section: Discussionsupporting

confidence: 70%

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Tholen

Wolanski

Stolze

et al. 2015

Journal of Biological Chemistry

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Background: Translational regulation might underlie the high expression levels of the protease cathepsin L (CTSL) associated with poor breast cancer prognosis. Results: Translation of CTSL mRNA is highly stress-resistant and promotes metastasis of murine breast cancer. Conclusion: CTSL mRNA circumvents translational shutdown in cancer-associated stress conditions. Significance: High expression of a metastasis promoting protease is maintained by translational regulation.

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Section: Discussionsupporting

confidence: 70%

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Tholen

Wolanski

Stolze

et al. 2015

Journal of Biological Chemistry

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“…5B). For example, elevated levels of the protease cathepsin L, a gene overexpressed in bigenic tumors, have been associated with increased tumor burden and decreased survival in human breast carcinoma (Foekens et al 1998;Harbeck et al 2000). …”

Section: Bigenic Tumors Express Higher Levels Of Markers Of Differentmentioning

confidence: 99%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

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Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

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“…The same reproach regarding the origin of cystatin C holds true when immunobiochemical methods are used for the determination of cystatin C levels in tissue homogenates. However, a large body of evidence proved the tissue homogenate levels of proteinases and inhibitors of various classes to be of significant clinical relevance (Foekens et al, 1998;Look et al, 2002).…”

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confidence: 99%

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

et al. 2004

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To determine the role of the cysteine proteinase inhibitor cystatin C in the invasive behavior of squamous cell carcinoma of the head and neck (SCCHN), Cystatin C protein level was measured in 82 pairs of primary tumour tissue and adjacent noncancerous mucosa, using the enzyme-linked immunosorbent assay. The median level of cystatin C in tumour tissue was 1.18 times lower than that in corresponding mucosa (P ¼ 0.031). In normal mucosa samples, the cystatin C level was influenced by the site of sampling: it was lower in nonlaryngeal tissue samples (oral cavity, oro-or hypopharynx) than in laryngeal samples (P ¼ 0.004). The tumour cystatin C level correlated inversely with pN-stage (P ¼ 0.047), whereas a trend of lower cystatin C levels was observed in the group with extranodal tumour extension compared to those with no extranodal spread (P ¼ 0.069). In univariate analysis, the patients with low tumour cystatin C levels exhibited poor disease-free survival (DFS, P ¼ 0.013) and disease-specific survival (DSS, P ¼ 0.013). In multivariate analysis, the most powerful predictor of survival was pN-stage (DFS: P ¼ 0.040, HR 2.78; DSS: P ¼ 0.011, HR 4.36,), followed by the cystatin C level (DFS: P ¼ 0.043, HR 0.22; DSS: P ¼ 0.067, HR 0.25). When comparing the prognostic strength of cystatin C to that of stefin A, another cysteine proteinase inhibitor, which emerged as the most significant prognosticator for survival in our previous study analysing the same cohort of patients, stefin A proved to be significantly more reliable predictor for both DFS and DSS than cystatin C. Our results indicate that cystatin C is implicated in the invasive behavior of SCCHN, and that there are variations in regulation of proteolytic pathways under nonmalignant conditions, inherent to individual subsites inside the upper aerodigestive tract. The correlation between high cystatin C levels and improved survival concurs with the concept of the protective role of high levels of cysteine proteinase inhibitors in tissue homogenates that has been previously suggested by the survival results in breast and lung carcinoma as well as SCCHN.

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Prognostic significance of cathepsins B and L in primary human breast cancer.

Abstract: CatB and catL levels measured in routinely prepared cytosols are strong parameters to predict the rate of relapse and the length of survival after treatment of the primary breast tumor.

Cited by 132 publications

References 25 publications

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

PPARγ signaling exacerbates mammary gland tumor development

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

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