Clinical Significance of Cathepsin D Concentration in Tumor Cytosol of Primary Breast Cancer

Rodrı́guez, Juan Carlos; Vízquez, J.; Corte, M.D.; Lamelas, Marı́a L.; Bongera, Miguel; Alvarez, A. M.; Salcedo, Mayte; González, Luis O.; Sínchez, M.; Vijande, M.; Muñiz, JL García; Vizoso, F

doi:10.1177/172460080502000204

Cited by 27 publications

(20 citation statements)

References 30 publications

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“…In accordance with our observations of increased ERα expression following FKBPL knockdown, high ERα levels have been associated with estrogen-independent signaling and endocrine therapy resistance (42). In addition, elevated cathepsin D levels in patient samples have been linked with early relapse (43) and reduced survival (44). FKBPL overexpression inhibited ligand-independent Ser 118 phosphorylation, suggesting that FKBPL may affect growth factor receptor-or mitogen-activated protein kinase (MAPK)-driven ERα phosphorylation, although this remains to be elucidated.…”

Section: Discussionsupporting

confidence: 72%

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

et al. 2010

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The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor α (ERα) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERα phosphorylation on Ser 118 in response to 17β-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome.

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Section: Discussionsupporting

confidence: 72%

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

et al. 2010

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“…In addition to these observations, there is now ample clinical evidence that up-regulation of these proteinases confers a poor prognosis in patients with a variety of malignancies [37][38][39]. The human cysteine cathepsin family comprises 11 Fig.…”

Section: Introductionmentioning

confidence: 99%

Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation

et al. 2018

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Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA doublestrand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest that CTSS inhibition is a good strategy for functional restoration of BRCA1 in breast cancers with reduced BRCA1 protein stability.

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“…This overproduction in breast cancer is correlated with a poor prognosis (Ferrandina et al, 1997;Foekens et al, 1999;Rodriguez et al, 2005). Human cath-D is synthesized as a 52-kDa precursor that is rapidly converted in the endosomes to form an active, 48-kDa, single-chain intermediate, and then in the lysosomes into the fully active mature protease, composed of a 34-kDa heavy chain and a 14-kDa light chain (Gieselmann et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

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The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1b-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231N cath-D, and pro-D231N cath-D all significantly inhibited LRP1 RIP by preventing LRP1b-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

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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.

Cited by 27 publications

References 30 publications

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

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