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Masaru Himeno - One of the best experts on this subject based on the ideXlab platform.

  • Cathepsin D Associates with Lysosomal Membranous Protein
    Biological & Pharmaceutical Bulletin, 1995
    Co-Authors: Yukio Nishimura, Masaru Himeno
    Abstract:

    The membrane-association of early biosynthetic form of Cathepsin D has been DemonstrateD in hepatoma cells, anD this membrane-association is not meDiateD by mannose 6-phosphate resiDues, implying that a mannose 6-phosphate receptor-inDepenDent mechanism operates in the sorting of Cathepsin D. In this paper, to Demonstrate whether Cathepsin D is associateD with the lysosomal membranes, an in vitro binDing experiment was carrieD out employing lysosomal Cathepsin D or microsomal proCathepsin D isolateD from rat liver. Immunoblotting analysis revealeD that an intermeDiate form of Cathepsin D was associateD with the lysosomal membranes ; this lysosomal membrane-associateD Cathepsin D was releaseD from the membranes by washing with Na2CO3 (pH 10.6) but not with solutions containing mannose 6-phosphate. This suggesteD that Cathepsin D associates with the membranes by ionic-interaction, anD that the membrane-associateD Cathepsin D resiDes as a peripheral membrane protein in the lysosomal membrane fraction. To confirm that the intermeDiate form of Cathepsin D specifically interacts with the lysosomal integral membrane proteins, the lysosomal membrane fraction was treateD with trypsin anD the binDing experiment was conDucteD. The result showeD that the binDing capacity of Cathepsin D to the lysosomal membranes was apparently abolisheD anD Cathepsin D DiD not rebinD to the membranes. These Data suggest that the intermeDiate form of Cathepsin D is preferentially recognizeD by the lysosomal membranous protein which complements the mannose 6-phosphate receptor-DepenDent intracellular sorting mechanism.

  • Intracellular Targeting of Lysosomal Cathepsin D in COS Cells.
    Journal of Biochemistry, 1995
    Co-Authors: Hiroaki Takeshima, Masaru Himeno, Masao Sakaguchi, Katsuyoshi Mihara, Tsuneo Omura, Kazuya Murakami, Yukio Nishimura
    Abstract:

    : Cathepsin D carries a mannose 6-phosphate sorting signal which is recognizeD by a specific mannose 6-phosphate receptor, presumably at the site of the trans Golgi network, which segregates Cathepsin D from the secretory proteins, anD results in targeting of the enzyme to the aciDic prelysosomal compartments anD lysosomes in mammalian cells. Recent eviDence implies that another sorting signal resiDes within the polypeptiDe backbone of the precursor Cathepsin D. To evaluate the role of the propeptiDe region of Cathepsin D in mannose 6-phosphate receptor-inDepenDent targeting to lysosomes, we prepareD a Deletion mutant of rat Cathepsin D lacking the propeptiDe portion anD analyzeD its intracellular targeting mechanism after transfection of the mutant cDNA as well as the wilD-type cDNA into COS cells. The glycosylateD mutant protein was retaineD intracellularly, anD extracellular release of mutant protein was not observeD after a 48 h chase. A cell fractionation experiment DemonstrateD that in the cells expressing the wilD-type Cathepsin D, the processeD form of 44 kDa Cathepsin D was recovereD in the Dense lysosomal fraction. In contrast, in the cells expressing the mutant protein, virtually all of the cell-associateD Cathepsin D was present in the light fraction which was enricheD in the marker enzyme NADPH cytochrome c reDuctase, anD this molecular form of Cathepsin D was not observeD in the Dense lysosomal fraction. An immunofluorescence stuDy revealeD that the Deletion mutant protein was accumulateD within the enDoplasmic reticulum, unlike the wilD-type protein. These results suggest that the mutant Cathepsin D is not correctly recognizeD by the intracellular sorting system in the enDoplasmic reticulum, implying that the propeptiDe region of Cathepsin D is essential for the export of Cathepsin D from the enDoplasmic reticulum.

  • Expression of Rat Cathepsin D cDNA in Saccharomyces Cerevisiae: Intracellular Sorting of Cathepsin D to Yeast Vacuole
    Advances in Experimental Medicine and Biology, 1995
    Co-Authors: Yukio Nishimura, Keitaro Kato, Hideaki Fujita, Masaru Himeno
    Abstract:

    Lysosomal Cathepsin D is a major aspartic proteinase anD is consiDereD to have physiological functions in intracellular protein DegraDation. Cathepsin D is one of the best characterizeD lysosomal proteinase for its intracellular protein sorting pathway in mammalian cells. Cathepsin D is synthesizeD as its preproform on the membrane-bounD polysomes of the rough ER membranes, anD the enzyme unDergoes co-translational cleavage of the NH2-terminal signal peptiDe in the rough ER membranes anD simultaneously the high-mannose type oligosacchariDe chains are aDDeD to form the glycosylateD proenzyme, then initially follows the secretory pathway. During the pathway from the ER to the Golgi complex, the mannose 6-phosphate resiDues are formeD on their oligosacchariDes anD the Cathepsin D carrying the mannose 6-phosphate signal are recognizeD in the Golgi complex by a specific receptor (MPR) which plays a critical role in the segregation anD targeting of lysosomal enzymes to the enDosomes anD lysosomes, anD the propeptiDe-portion of Cathepsin D is processeD anD is activateD unDer aciDic conDitions upon the arrival of the enzyme in the lysosomes (1–4).

  • Expression of Rat Cathepsin D cDNA in Saccharomyces cerevisiae: Implications for Intracellular Targeting of Cathepsin D to Vacuoles
    Journal of Biochemistry, 1995
    Co-Authors: Yukio Nishimura, Hiroaki Takeshima, Masao Sakaguchi, Katsuyoshi Mihara, Tsuneo Omura, Keitaro Kato, Masaru Himeno
    Abstract:

    : To investigate the intracellular transport mechanisms of lysosomal Cathepsin D in yeast cells, we proDuceD Cathepsin D in Saccharomyces cerevisiae by placing the coDing region unDer the control of the promoter of the yeast glyceralDehyDe-3-phosphate DehyDrogenase (GAPDH) gene. Immunoblotting analysis by the use of an antiboDy specific for rat Cathepsin D coDing sequence proDuceD an intermeDiate species which haD a slightly higher molecular weight than that of the mature Cathepsin D. Cell fractionation experiments DemonstrateD that the Cathepsin D polypeptiDe was colocalizeD to the yeast vacuoles with the marker enzyme carboxypeptiDase Y in a Ficoll step graDient. A biosynthesis stuDy with pulse-chase kinetic analysis revealeD that the precursor polypeptiDe was accurately sorteD to the yeast vacuoles as DetermineD by cell fractionation, anD that N-linkeD carbohyDrate moDifications were not requireD for vacuolar sorting of this protein. To eluciDate the role of the propeptiDe region of Cathepsin D, which might function in the intracellular targeting to the vacuole, a Deletion mutant of Cathepsin D lacking the propeptiDe was prepareD anD its intracellular targeting was examineD after transfection into yeast cells. Immunoblotting analysis DemonstrateD that the propeptiDe-DeleteD mutant protein was recovereD in a low quantity as compareD with that in the case of yeast cells expressing the wilD-type protein in the isolateD vacuolar fraction. Immunofluorescence analysis revealeD that the Deletion mutant protein appeareD to be accumulateD within the intracellular small vesicles but not in the carboxypeptiDase Y-positive vacuoles. Overall, these results inDicate that the rat Cathepsin D precursor polypeptiDe is recognizeD by mechanisms similar to those involveD in the intracellular sorting of vacuolar proteins through the ER/Golgi/vacuolar sorting pathway in yeast cells, anD that the propeptiDe has an important function in translocation of the Cathepsin D polypeptiDe to the vacuole.

Yukio Nishimura - One of the best experts on this subject based on the ideXlab platform.

  • Cathepsin D Associates with Lysosomal Membranous Protein
    Biological & Pharmaceutical Bulletin, 1995
    Co-Authors: Yukio Nishimura, Masaru Himeno
    Abstract:

    The membrane-association of early biosynthetic form of Cathepsin D has been DemonstrateD in hepatoma cells, anD this membrane-association is not meDiateD by mannose 6-phosphate resiDues, implying that a mannose 6-phosphate receptor-inDepenDent mechanism operates in the sorting of Cathepsin D. In this paper, to Demonstrate whether Cathepsin D is associateD with the lysosomal membranes, an in vitro binDing experiment was carrieD out employing lysosomal Cathepsin D or microsomal proCathepsin D isolateD from rat liver. Immunoblotting analysis revealeD that an intermeDiate form of Cathepsin D was associateD with the lysosomal membranes ; this lysosomal membrane-associateD Cathepsin D was releaseD from the membranes by washing with Na2CO3 (pH 10.6) but not with solutions containing mannose 6-phosphate. This suggesteD that Cathepsin D associates with the membranes by ionic-interaction, anD that the membrane-associateD Cathepsin D resiDes as a peripheral membrane protein in the lysosomal membrane fraction. To confirm that the intermeDiate form of Cathepsin D specifically interacts with the lysosomal integral membrane proteins, the lysosomal membrane fraction was treateD with trypsin anD the binDing experiment was conDucteD. The result showeD that the binDing capacity of Cathepsin D to the lysosomal membranes was apparently abolisheD anD Cathepsin D DiD not rebinD to the membranes. These Data suggest that the intermeDiate form of Cathepsin D is preferentially recognizeD by the lysosomal membranous protein which complements the mannose 6-phosphate receptor-DepenDent intracellular sorting mechanism.

  • Intracellular Targeting of Lysosomal Cathepsin D in COS Cells.
    Journal of Biochemistry, 1995
    Co-Authors: Hiroaki Takeshima, Masaru Himeno, Masao Sakaguchi, Katsuyoshi Mihara, Tsuneo Omura, Kazuya Murakami, Yukio Nishimura
    Abstract:

    : Cathepsin D carries a mannose 6-phosphate sorting signal which is recognizeD by a specific mannose 6-phosphate receptor, presumably at the site of the trans Golgi network, which segregates Cathepsin D from the secretory proteins, anD results in targeting of the enzyme to the aciDic prelysosomal compartments anD lysosomes in mammalian cells. Recent eviDence implies that another sorting signal resiDes within the polypeptiDe backbone of the precursor Cathepsin D. To evaluate the role of the propeptiDe region of Cathepsin D in mannose 6-phosphate receptor-inDepenDent targeting to lysosomes, we prepareD a Deletion mutant of rat Cathepsin D lacking the propeptiDe portion anD analyzeD its intracellular targeting mechanism after transfection of the mutant cDNA as well as the wilD-type cDNA into COS cells. The glycosylateD mutant protein was retaineD intracellularly, anD extracellular release of mutant protein was not observeD after a 48 h chase. A cell fractionation experiment DemonstrateD that in the cells expressing the wilD-type Cathepsin D, the processeD form of 44 kDa Cathepsin D was recovereD in the Dense lysosomal fraction. In contrast, in the cells expressing the mutant protein, virtually all of the cell-associateD Cathepsin D was present in the light fraction which was enricheD in the marker enzyme NADPH cytochrome c reDuctase, anD this molecular form of Cathepsin D was not observeD in the Dense lysosomal fraction. An immunofluorescence stuDy revealeD that the Deletion mutant protein was accumulateD within the enDoplasmic reticulum, unlike the wilD-type protein. These results suggest that the mutant Cathepsin D is not correctly recognizeD by the intracellular sorting system in the enDoplasmic reticulum, implying that the propeptiDe region of Cathepsin D is essential for the export of Cathepsin D from the enDoplasmic reticulum.

  • Expression of Rat Cathepsin D cDNA in Saccharomyces Cerevisiae: Intracellular Sorting of Cathepsin D to Yeast Vacuole
    Advances in Experimental Medicine and Biology, 1995
    Co-Authors: Yukio Nishimura, Keitaro Kato, Hideaki Fujita, Masaru Himeno
    Abstract:

    Lysosomal Cathepsin D is a major aspartic proteinase anD is consiDereD to have physiological functions in intracellular protein DegraDation. Cathepsin D is one of the best characterizeD lysosomal proteinase for its intracellular protein sorting pathway in mammalian cells. Cathepsin D is synthesizeD as its preproform on the membrane-bounD polysomes of the rough ER membranes, anD the enzyme unDergoes co-translational cleavage of the NH2-terminal signal peptiDe in the rough ER membranes anD simultaneously the high-mannose type oligosacchariDe chains are aDDeD to form the glycosylateD proenzyme, then initially follows the secretory pathway. During the pathway from the ER to the Golgi complex, the mannose 6-phosphate resiDues are formeD on their oligosacchariDes anD the Cathepsin D carrying the mannose 6-phosphate signal are recognizeD in the Golgi complex by a specific receptor (MPR) which plays a critical role in the segregation anD targeting of lysosomal enzymes to the enDosomes anD lysosomes, anD the propeptiDe-portion of Cathepsin D is processeD anD is activateD unDer aciDic conDitions upon the arrival of the enzyme in the lysosomes (1–4).

  • Expression of Rat Cathepsin D cDNA in Saccharomyces cerevisiae: Implications for Intracellular Targeting of Cathepsin D to Vacuoles
    Journal of Biochemistry, 1995
    Co-Authors: Yukio Nishimura, Hiroaki Takeshima, Masao Sakaguchi, Katsuyoshi Mihara, Tsuneo Omura, Keitaro Kato, Masaru Himeno
    Abstract:

    : To investigate the intracellular transport mechanisms of lysosomal Cathepsin D in yeast cells, we proDuceD Cathepsin D in Saccharomyces cerevisiae by placing the coDing region unDer the control of the promoter of the yeast glyceralDehyDe-3-phosphate DehyDrogenase (GAPDH) gene. Immunoblotting analysis by the use of an antiboDy specific for rat Cathepsin D coDing sequence proDuceD an intermeDiate species which haD a slightly higher molecular weight than that of the mature Cathepsin D. Cell fractionation experiments DemonstrateD that the Cathepsin D polypeptiDe was colocalizeD to the yeast vacuoles with the marker enzyme carboxypeptiDase Y in a Ficoll step graDient. A biosynthesis stuDy with pulse-chase kinetic analysis revealeD that the precursor polypeptiDe was accurately sorteD to the yeast vacuoles as DetermineD by cell fractionation, anD that N-linkeD carbohyDrate moDifications were not requireD for vacuolar sorting of this protein. To eluciDate the role of the propeptiDe region of Cathepsin D, which might function in the intracellular targeting to the vacuole, a Deletion mutant of Cathepsin D lacking the propeptiDe was prepareD anD its intracellular targeting was examineD after transfection into yeast cells. Immunoblotting analysis DemonstrateD that the propeptiDe-DeleteD mutant protein was recovereD in a low quantity as compareD with that in the case of yeast cells expressing the wilD-type protein in the isolateD vacuolar fraction. Immunofluorescence analysis revealeD that the Deletion mutant protein appeareD to be accumulateD within the intracellular small vesicles but not in the carboxypeptiDase Y-positive vacuoles. Overall, these results inDicate that the rat Cathepsin D precursor polypeptiDe is recognizeD by mechanisms similar to those involveD in the intracellular sorting of vacuolar proteins through the ER/Golgi/vacuolar sorting pathway in yeast cells, anD that the propeptiDe has an important function in translocation of the Cathepsin D polypeptiDe to the vacuole.

I. O. Ellis - One of the best experts on this subject based on the ideXlab platform.

  • Cathepsin D in primary breast carcinoma: ADverse prognosis is associateD with expression of Cathepsin D in stromal cells
    Breast Cancer Research and Treatment, 1995
    Co-Authors: A. E. M. A. O'donoghue, D. N. Poller, J. A. Bell, M. H. Galea, C. W. Elston, R. W. Blamey, I. O. Ellis
    Abstract:

    The immunohistochemical expression of the aspartyl protease enzyme Cathepsin D was examineD in a consecutive series of 103 primary operable breast carcinomas with the polyclonal antiboDy NCL-CDp. Expression of Cathepsin D was iDentifieD within the epithelial anD stromal components of all tumours examineD. No significant associations of increaseD Cathepsin D expression in the epithelial tumour component with conventional prognostic inDices such as tumour size, graDe, lymph noDe stage, or patient survival were iDentifieD. However, significant associations of increaseD stromal Cathepsin D expression anD high tumour graDe, χ ^2 = 11.40 (Df = 2), p = 0.003; increaseD tenDency to local recurrence, χ ^2 = 6.87 (Df = 1), p = 0.009; regional recurrence, χ ^2 = 7.44 (Df = 1), p = 0.006; poorer Disease free survival, χ ^2 = 14.9 (Df = 1), p = 0.0001; anD poorer overall patient survival, χ ^2 = 6.90 (Df = 1), p = 0.0086, were iDentifieD. Cathepsin D expression is present in all breast tumours. Stromal Cathepsin D expression is a neglecteD immunohistochemical prognostic parameter which coulD explain some of the previous apparently conflicting reports concerning the effect on patient prognosis of biochemical (i.e. total) anD immunohistochemical estimations of Cathepsin D in breast cancers.

J G M Klijn - One of the best experts on this subject based on the ideXlab platform.

  • Cathepsin D in primary breast cancer prognostic evaluation involving 2810 patients
    British Journal of Cancer, 1999
    Co-Authors: J A Foekens, Maxime P Look, Boltde J Vries, M Meijervan E Gelder, W L J Van Putten, J G M Klijn
    Abstract:

    There is controversy regarDing the prognostic value of Cathepsin-D in primary breast cancer. An increaseD level of Cathepsin-D in tumour extracts has been founD to be associateD with a poor relapse-free anD overall survival. StuDies performeD with immunohistochemistry or Western blotting have proDuceD Diverse results. We have analyseD 2810 cytosolic extracts obtaineD from human primary breast tumours for Cathepsin-D expression, anD have correlateD their levels with prognosis. The meDian follow-up of the patients still alive was 88 months. Patients with high Cathepsin-D levels haD a significantly worse relapse-free anD overall survival, also in multivariate analysis (P < 0.0001). ADjuvant therapy which was associateD with an improveD prognosis in noDe-positive patients in univariate analysis, also significantly aDDeD to the multivariate moDels for relapse-free anD overall survival. There were no statistically significant interactions between the levels of Cathepsin-D anD any of the classical prognostic factors in analysis for relapse-free survival, suggesting that the prognostic value of Cathepsin-D is not Different in the various subgroups of patients. InDeeD, multivariate analyses in subgroups of noDe-negative anD -positive patients, pre- anD post-menopausal patients, anD their combinations, showeD that tumours with high Cathepsin-D values haD a significantly poor relapse-free survival, with relative hazarD rates ranging from 1.3 to 1.5, compareD with tumours with low Cathepsin-D levels. The results presenteD here on 2810 patients confirm that high cytosolic Cathepsin-D values are associateD with poor prognosis in human primary breast cancer. © 1999 Cancer Research Campaign

Henri Rochefort - One of the best experts on this subject based on the ideXlab platform.

  • ImmunoraDiometric assay of pro-Cathepsin D in breast cancer cytosol: Relative prognostic value versus total Cathepsin D
    European Journal of Cancer, 2004
    Co-Authors: Jean-paul Brouillet, Frédérique Spyratos, Kamel Hacène, J. Fauque, Gilles Freiss, F. Dupont, Thierry Maudelonde, Henri Rochefort
    Abstract:

    Abstract In breast cancer cell lines, the maturation of pro-Cathepsin D into enzymatically active Cathepsin D is altereD, leaDing to its increaseD secretion. In orDer to specifically assay pro-Cathepsin D (52 kD form) in breast cancer cytosol, we monitoreD a soliD phase sanDwich raDioimmunoassay using D9H8 anD D7E3 monoclonal antiboDies raiseD against human pro-Cathepsin D from MCF7 cells. Pro-Cathepsin D was assayeD in 108 primary breast cancer cytosols in which total Cathepsin D was previously founD to be correlateD with metastasis. Pro-Cathepsin D concentrations were founD to be correlateD with total Cathepsin D anD with lymph noDe invasion, anD was slightly higher in premenopausal patients. By contrast, Cox multiparametric analysis showeD that pro-Cathepsin D status haD no prognostic value for survival, or metastasis free survival contrary to total Cathepsin D status. This first stuDy shows the technical valiDity of the pro-Cathepsin D assay but inDicates that it has less value as a prognostic marker than total Cathepsin D. This stuDy also shows that the proportion of pro-Cathepsin D recovereD in vivo (1–6%) is much less than that proDuceD in cell lines anD suggests that the secreteD pro-enzyme might be activateD in the tumour extracellularly or following its reinternalisation.

  • Cathepsin D in breast cancer mechanisms anD clinical applications a 1999 overview
    Clinica Chimica Acta, 2000
    Co-Authors: Henri Rochefort, Marcel Garcia, Murielle Glondu, Valerie Laurent, Emmanuelle Liaudet, Pascal Roger
    Abstract:

    Abstract A short review of the literature first confirms the clinical value of Cathepsin D as a prognostic marker in breast cancer, when using well stanDarDizeD assays. We then summarize results of stuDies, mostly performeD in our laboratory, aimeD at unDerstanDing the effect of Cathepsin D overexpression on metastasis anD the molecular mechanisms involveD. Cathepsin D–cDNA transfection increases tumor cell proliferation in vitro anD the metastatic potential of 3Y1-AD12 embryonic rat tumorigenic cells when injecteD in vivo into nuDe mice. The mechanism by which Cathepsin D increases the inciDence of clinical metastasis involves increaseD cell growth anD DecreaseD contact inhibition rather than escape of cancer cells through the basement membrane. Different mechanisms are consiDereD to explain this mitogenic activity. Cathepsin D coulD act as a protease following its activation at an aciDic pH, or as a liganD of Different membrane receptors at a more neutral pH. In this case Cathepsin D can Displace IGFII from the mannose-6-phosphate/IGFII receptor to the IGFI receptor or activate another membrane receptor to be iDentifieD. The nature of the mechanisms involveD in vivo may DepenD on the micro environment of the tumor cells. These stuDies shoulD guiDe in the Development of new therapies aimeD at inhibiting the Deleterious effect of overexpresseD Cathepsin D.

  • Cathepsin D: a protease involveD in breast cancer metastasis
    Cancer and Metastasis Reviews, 1990
    Co-Authors: Henri Rochefort, Françoise Capony, Marcel Garcia
    Abstract:

    Cathepsin D is an aciDic lysosomal protease present in all cells. In estrogen receptor positive anD negative breast cancer cell lines, the mRNA coDing for pro-Cathepsin D is overexpresseD anD sorting anD maturation of the pro-enzyme are altereD, via possibly saturation of the Man-6-P/IGF-II receptor, leaDing to accumulation of the active proteinase in large enDosomes anD to secretion of the precursor (52K protein). In MCF7 cells, the Cathepsin D mRNA is inDuceD Directly anD transcriptionally by estrogens anD inDirectly by growth factors. In patients, there is a significant correlation between high Cathepsin D concentrations in the cytosol of primary breast cancer anD Development of metastasis. This marker is inDepenDent of other prognostic factors anD appears to be particularly useful in axillary noDe-negative tumors. Transfection of a human cDNA Cathepsin D expression vector unDer the control of SV40 promoter increases the metastatic potential of 3YA1-AD12 rat tumorigenic cells when intravenously injecteD into nuDe mice. The mechanism of Cathepsin D-inDuceD metastasis is currently unknown. These results inDicate that overexpression of Cathepsin D might facilitate breast cancer metastasis, suggesting new possible therapeutic approaches.

  • Cathepsin D in breast cancer.
    Breast Cancer Research and Treatment, 1990
    Co-Authors: Henri Rochefort
    Abstract:

    Cathepsin D is an aciDic lysosomal protease present in all cells. In estrogen receptor positive anD negative breast cancer cell lines, the mRNA coDing for pro-Cathepsin D is overexpresseD anD sorting anD maturation of the pro-enzyme are altereD, leaDing to accumulation of the active proteinase in large enDosomes anD to secretion of the precursor (52K protein). In MCF7 cells, the Cathepsin D mRNA is inDuceD Directly anD transcriptionally by estrogens anD inDirectly by growth factors.In vitro, pro-Cathepsin D is an autocrine mitogen on breast cancer cells anD can be auto-activateD to DegraDe extracellular matrix anD proteoglycans anD to activate other proteinases in aciDic microenvironments. In patients, there is a significant correlation between high Cathepsin D concentrations in the cytosol of primary breast cancer anD Development of metastasis. This marker is inDepenDent of other prognostic factors anD appears to be particularly useful in lymph noDe-negative tumors. These results suggest that overexpression anD possible Derouting of Cathepsin D plays an important role in invasion anD metastasis of breast cancer.

  • Biological anD clinical significance of Cathepsin D in breast cancer.
    Seminars in Cancer Biology, 1990
    Co-Authors: Henri Rochefort
    Abstract:

    : Cathepsin D is an aciDic lysosomal protease present in all cells. In breast cancer cells, pro-Cathepsin D expression anD secretion are markeDly increaseD anD its processing is altereD. This protease is inDuceD by estrogens anD growth factors. In vitro, pro-Cathepsin D is an autocrine mitogen on breast cancer cells anD can be auto-activateD to DegraDe extracellular matrix anD proteoglycans in aciDic microenvironment. In patients, there is a significant correlation between high Cathepsin D concentrations in the cytosol of primary breast cancer anD Development of metastasis. This marker is inDepenDent of other prognostic factors anD appears to be particularly useful in lymph noDe-negative tumors. These results suggest that Derouting anD overexpression of Cathepsin D plays an important role in invasion anD metastasis of breast cancer cells.