Role of Cathepsins, in Particular Cathepsins B and D in Breast Cancer: Mechanisms and Clinical Implications

  • Anuradha Ratna
  • Salil K. DasEmail author


Consistent with the biological relevance of cathepsins B and D, their overexpression, translational or post-translational modifications, and mitogenic effects are hallmarks of breast cancer. Several studies have established a link between increased expression of cathepsins B and D and tumor growth, invasion, and metastasis. This review outlines the potential role of these two cathepsins, specifically in breast cancer, and different mechanisms involved during tumor progression and metastasis. The development of various therapeutic strategies, including specific inhibitors, gene targeted therapy, and antibodies against cathepsins in an attempt to curb breast tumor progression holds a promising future. However, from a translational perspective, further extensive studies are needed in order to unravel the therapeutic abilities of cathepsins B and D in controlling breast cancer.


Cathepsin B Cathepsin D Breast cancer Overexpression Metastasis Biomarker Cancer therapy 



The authors acknowledge the support from Fuji Oil Company, Osaka, Japan, and the Meharry Translational Research Center (MeTRC: NIH grant 5U54MD007593). The authors like to thank the Meharry Office for Scientific Editing and Publications (NIH endowment S21MD000104) for proofreading.


  1. 1.
    Willstatter R, Bamann E (1929) Über die Proteasen der Magenschleimhaut. Erste Abhandlung über die Enzyme der Leukozyten. Hoppe-Seylers Z Physiol Chem 180:127–143CrossRefGoogle Scholar
  2. 2.
    Anson ML (1940) The Purification of Cathepsin. J Gen Physiol 23:695–704PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F (1955) Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J 60:604–617PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kuester D, Lippert H, Roessner A, Krueger S (2008) The cathepsin family and their role in colorectal cancer. Pathol Res Pract 204:491–500PubMedCrossRefGoogle Scholar
  5. 5.
    Brix K, Dunkhorst A, Mayer K, Jordans S (2008) Cysteine cathepsins: cellular roadmap to different functions. Biochimie 90:194–207PubMedCrossRefGoogle Scholar
  6. 6.
    Brix K, Jordans S (2005) Watching proteases in action. Nat Chem Biol 1:186–187PubMedCrossRefGoogle Scholar
  7. 7.
    Lecaille F, Bromme D, Lalmanach G (2008) Biochemical properties and regulation of cathepsin K activity. Biochimie 90:208–226PubMedCrossRefGoogle Scholar
  8. 8.
    Fonovic M, Turk B (2014) Cysteine cathepsins and their potential in clinical therapy and biomarker discovery. Proteomics Clin Appl 8:416–426PubMedCrossRefGoogle Scholar
  9. 9.
    Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40:D343–D350PubMedCrossRefGoogle Scholar
  10. 10.
    Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B (2007) Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 13:387–403PubMedCrossRefGoogle Scholar
  11. 11.
    Honey K, Rudensky AY (2003) Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 3:472–482PubMedCrossRefGoogle Scholar
  12. 12.
    Stoch SA, Wagner JA (2008) Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 83:172–176PubMedCrossRefGoogle Scholar
  13. 13.
    Deal C (2009) Potential new drug targets for osteoporosis. Nat Clin Pract Rheumatol 5:20–27PubMedCrossRefGoogle Scholar
  14. 14.
    Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008) Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J Biol Chem 283:35652–35659PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kayser K, Richter N, Hufnagl P, Kayser G, Kos J, Werle B (2003) Expression, proliferation activity and clinical significance of cathepsin B and cathepsin L in operated lung cancer. Anticancer Res 23:2767–2772PubMedGoogle Scholar
  16. 16.
    Illy C, Quraishi O, Wang J, Purisima E, Vernet T, Mort JS (1997) Role of the occluding loop in cathepsin B activity. J Biol Chem 272:1197–1202PubMedCrossRefGoogle Scholar
  17. 17.
    Musil D, Zucic D, Turk D, Engh RA, Mayr I, Huber R, Popovic T, Turk V, Towatari T, Katunuma N et al (1991) The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. EMBO J 10:2321–2330PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Keppler D, Sloane BF (1996) Cathepsin B: multiple enzyme forms from a single gene and their relation to cancer. Enzym Protein 49:94–105CrossRefGoogle Scholar
  19. 19.
    Buck MR, Karustis DG, Day NA, Honn KV, Sloane BF (1992) Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem J 282:273–278PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Mai J, Sameni M, Mikkelsen T, Sloane BF (2002) Degradation of extracellular matrix protein tenascin-C by cathepsin B: an interaction involved in the progression of gliomas. Biol Chem 383:1407–1413PubMedCrossRefGoogle Scholar
  21. 21.
    Gocheva V, Zeng W, Ke D, Klimstra D, Reinheckel T, Peters C, Hanahan D, Joyce JA (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20:543–556PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Quraishi O, Nagler DK, Fox T, Sivaraman J, Cygler M, Mort JS, Storer AC (1999) The occluding loop in cathepsin B defines the pH dependence of inhibition by its propeptide. Biochemistry 38:5017–5023PubMedCrossRefGoogle Scholar
  23. 23.
    Podgorski I, Sloane BF (2003) Cathepsin B and its role(s) in cancer progression. Biochem Soc Symp 263–276Google Scholar
  24. 24.
    Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6:764–775PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Andl CD, McCowan KM, Allison GL, Rustgi AK (2010) Cathepsin B is the driving force of esophageal cell invasion in a fibroblast-dependent manner. Neoplasia 12:485–498PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Vasiljeva O, Papazoglou A, Kruger A, Brodoefel H, Korovin M, Deussing J, Augustin N, Nielsen BS, Almholt K, Bogyo M, Peters C, Reinheckel T (2006) Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res 66:5242–5250PubMedCrossRefGoogle Scholar
  27. 27.
    Vasiljeva O, Korovin M, Gajda M, Brodoefel H, Bojic L, Kruger A, Schurigt U, Sevenich L, Turk B, Peters C, Reinheckel T (2008) Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice. Oncogene 27:4191–4199PubMedCrossRefGoogle Scholar
  28. 28.
    Benes P, Vetvicka V, Fusek M (2008) Cathepsin D-many functions of one aspartic protease. Crit Rev Oncol Hematol 68:12–28PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Khalkhali-Ellis Z, Hendrix MJ (2014) Two faces of cathepsin D: physiological guardian angel and pathological demon. Biol Med 6:206CrossRefGoogle Scholar
  30. 30.
    Masson O, Bach AS, Derocq D, Prebois C, Laurent-Matha V, Pattingre S, Liaudet-Coopman E (2010) Pathophysiological functions of cathepsin D: targeting its catalytic activity versus its protein binding activity? Biochimie 92:1635–1643PubMedCrossRefGoogle Scholar
  31. 31.
    Bussemakers MJ, Schalken JA (1996) The role of cell adhesion molecules and proteases in tumor invasion and metastasis. World J Urol 14:151–156PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia M, Derocq D, Pujol P, Rochefort H (1990) Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency. Oncogene 5:1809–1814PubMedGoogle Scholar
  33. 33.
    Koblinski JE, Ahram M, Sloane BF (2000) Unraveling the role of proteases in cancer. Clin Chim Acta 291:113–135PubMedCrossRefGoogle Scholar
  34. 34.
    Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3:489–501PubMedCrossRefGoogle Scholar
  35. 35.
    Strathdee G (2002) Epigenetic versus genetic alterations in the inactivation of E-cadherin. Semin Cancer Biol 12:373–379PubMedCrossRefGoogle Scholar
  36. 36.
    Joyce JA, Baruch A, Chehade K, Meyer-Morse N, Giraudo E, Tsai FY, Greenbaum DC, Hager JH, Bogyo M, Hanahan D (2004) Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5:443–453CrossRefPubMedGoogle Scholar
  37. 37.
    Sameni M, Elliott E, Ziegler G, Fortgens PH, Dennison C, Sloane BF (1995) Cathepsin B and D are localized at the surface of human breast cancer cells. Pathol Oncol Res 1:43–53PubMedCrossRefGoogle Scholar
  38. 38.
    Castiglioni T, Merino MJ, Elsner B, Lah TT, Sloane BF, Emmert-Buck MR (1994) Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer. Hum Pathol 25:857–862PubMedCrossRefGoogle Scholar
  39. 39.
    Weber E, Barbulescu E, Medek R, Reinheckel T, Sameni M, Anbalagan A, Moin K, Sloane BF (2015) Cathepsin B-deficient mice as source of monoclonal anti-cathepsin B antibodies. Biol Chem 396:277–281PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Rafn B, Nielsen CF, Andersen SH, Szyniarowski P, Corcelle-Termeau E, Valo E, Fehrenbacher N, Olsen CJ, Daugaard M, Egebjerg C, Bottzauw T, Kohonen P, Nylandsted J, Hautaniemi S, Moreira J, Jaattela M, Kallunki T (2012) ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Mol Cell 45:764–776PubMedCrossRefGoogle Scholar
  41. 41.
    Gopinathan A, Denicola GM, Frese KK, Cook N, Karreth FA, Mayerle J, Lerch MM, Reinheckel T, Tuveson DA (2012) Cathepsin B promotes the progression of pancreatic ductal adenocarcinoma in mice. Gut 61:877–884PubMedCrossRefGoogle Scholar
  42. 42.
    Sevenich L, Werner F, Gajda M, Schurigt U, Sieber C, Muller S, Follo M, Peters C, Reinheckel T (2011) Transgenic expression of human cathepsin B promotes progression and metastasis of polyoma-middle-T-induced breast cancer in mice. Oncogene 30:54–64PubMedCrossRefGoogle Scholar
  43. 43.
    Pavlova A, Bjork I (2003) Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases. Biochemistry 42:11326–11333PubMedCrossRefGoogle Scholar
  44. 44.
    Pol E, Bjork I (2001) Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases. Protein Sci 10:1729–1738PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Mai J, Finley RL Jr, Waisman DM, Sloane BF (2000) Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells. J Biol Chem 275:12806–12812PubMedCrossRefGoogle Scholar
  46. 46.
    Hughes SJ, Glover TW, Zhu XX, Kuick R, Thoraval D, Orringer MB, Beer DG, Hanash S (1998) A novel amplicon at 8p22-23 results in overexpression of cathepsin B in esophageal adenocarcinoma. Proc Natl Acad Sci U S A 95:12410–12415PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Seth P, Mahajan VS, Chauhan SS (2003) Transcription of human cathepsin L mRNA species hCATL B from a novel alternative promoter in the first intron of its gene. Gene 321:83–91PubMedCrossRefGoogle Scholar
  48. 48.
    Yan S, Sloane BF (2003) Molecular regulation of human cathepsin B: implication in pathologies. Biol Chem 384:845–854PubMedGoogle Scholar
  49. 49.
    Qian F, Frankfater A, Chan SJ, Steiner DF (1991) The structure of the mouse cathepsin B gene and its putative promoter. DNA Cell Biol 10:159–168PubMedCrossRefGoogle Scholar
  50. 50.
    Konduri S, Lakka SS, Tasiou A, Yanamandra N, Gondi CS, Dinh DH, Olivero WC, Gujrati M, Rao JS (2001) Elevated levels of cathepsin B in human glioblastoma cell lines. Int J Oncol 19:519–524PubMedGoogle Scholar
  51. 51.
    Sitabkhan Y, Frankfater A (2007) Differences in the expression of cathepsin B in B16 melanoma metastatic variants depend on transcription factor Sp1. DNA Cell Biol 26:673–682PubMedCrossRefGoogle Scholar
  52. 52.
    Fais S (2007) Cannibalism: a way to feed on metastatic tumors. Cancer Lett 258:155–164PubMedCrossRefGoogle Scholar
  53. 53.
    Somanna A, Mundodi V, Gedamu L (2002) Functional analysis of cathepsin B-like cysteine proteases from Leishmania donovani complex. Evidence for the activation of latent transforming growth factor beta. J Biol Chem 277:25305–25312PubMedCrossRefGoogle Scholar
  54. 54.
    Kostoulas G, Lang A, Nagase H, Baici A (1999) Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases. FEBS Lett 455:286–290PubMedCrossRefGoogle Scholar
  55. 55.
    Berquin IM, Yan S, Katiyar K, Huang L, Sloane BF, Troen BR (1999) Differentiating agents regulate cathepsin B gene expression in HL-60 cells. J Leukoc Biol 66:609–616PubMedCrossRefGoogle Scholar
  56. 56.
    Vignon F, Capony F, Chambon M, Freiss G, Garcia M, Rochefort H (1986) Autocrine growth stimulation of the MCF 7 breast cancer cells by the estrogen-regulated 52 K protein. Endocrinology 118:1537–1545PubMedCrossRefGoogle Scholar
  57. 57.
    Faridi JS, Mohan S, De Leon DD (2004) Modulation of cathepsin D routing by IGF-II involves IGF-II binding to IGF-II/M6P receptor in MCF-7 breast cancer cells. Growth Factors 22:169–177PubMedCrossRefGoogle Scholar
  58. 58.
    Vashishta A, Ohri SS, Proctor M, Fusek M, Vetvicka V (2007) Ribozyme-targeting procathepsin D and its effect on invasion and growth of breast cancer cells: an implication in breast cancer therapy. Int J Oncol 30:1223–1230PubMedGoogle Scholar
  59. 59.
    Ohri SS, Vashishta A, Proctor M, Fusek M, Vetvicka V (2007) Depletion of procathepsin D gene expression by RNA interference: a potential therapeutic target for breast cancer. Cancer Biol Ther 6:1081–1087PubMedCrossRefGoogle Scholar
  60. 60.
    Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H (1989) Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res 49:3904–3909PubMedGoogle Scholar
  61. 61.
    Lenarcic B, Kos J, Dolenc I, Lucovnik P, Krizaj I, Turk V (1988) Cathepsin D inactivates cysteine proteinase inhibitors, cystatins. Biochem Biophys Res Commun 154:765–772PubMedCrossRefGoogle Scholar
  62. 62.
    Stewart AJ, Piggott NH, May FE, Westley BR (1994) Mitogenic activity of procathepsin D purified from conditioned medium of breast-cancer cells by affinity chromatography on pepstatinyl agarose. Int J Cancer 57:715–718PubMedCrossRefGoogle Scholar
  63. 63.
    Liaudet E, Derocq D, Rochefort H, Garcia M (1995) Transfected cathepsin D stimulates high density cancer cell growth by inactivating secreted growth inhibitors. Cell Growth Differ 6:1045–1052PubMedGoogle Scholar
  64. 64.
    Spyratos F, Maudelonde T, Brouillet JP, Brunet M, Defrenne A, Andrieu C, Hacene K, Desplaces A, Rouesse J, Rochefort H (1989) Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet 2:1115–1118PubMedCrossRefGoogle Scholar
  65. 65.
    Mathieu M, Rochefort H, Barenton B, Prebois C, Vignon F (1990) Interactions of cathepsin-D and insulin-like growth factor-II (IGF-II) on the IGF-II/mannose-6-phosphate receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II. Mol Endocrinol 4:1327–1335PubMedCrossRefGoogle Scholar
  66. 66.
    Briozzo P, Badet J, Capony F, Pieri I, Montcourrier P, Barritault D, Rochefort H (1991) MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: a permissive role of cathepsin D. Exp Cell Res 194:252–259PubMedCrossRefGoogle Scholar
  67. 67.
    Fehrenbacher N, Jaattela M (2005) Lysosomes as targets for cancer therapy. Cancer Res 65:2993–2995PubMedCrossRefGoogle Scholar
  68. 68.
    Rochefort H, Cavailles V, Augereau P, Capony F, Maudelonde T, Touitou I, Garcia M (1989) Overexpression and hormonal regulation of pro-cathepsin D in mammary and endometrial cancer. J Steroid Biochem 34:177–182PubMedCrossRefGoogle Scholar
  69. 69.
    Cavailles V, Garcia M, Rochefort H (1989) Regulation of cathepsin-D and pS2 gene expression by growth factors in MCF7 human breast cancer cells. Mol Endocrinol 3:552–558PubMedCrossRefGoogle Scholar
  70. 70.
    Cavailles V, Augereau P, Rochefort H (1993) Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells. Proc Natl Acad Sci USA 90:203–207PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Huang L, Liu Z, Chen S, Liu Y, Shao Z (2013) A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index. PLoS ONE 8:e83081PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Giamarchi C, Solanas M, Chailleux C, Augereau P, Vignon F, Rochefort H, Richard-Foy H (1999) Chromatin structure of the regulatory regions of pS2 and cathepsin D genes in hormone-dependent and -independent breast cancer cell lines. Oncogene 18:533–541PubMedCrossRefGoogle Scholar
  73. 73.
    Foekens JA, Look MP, Bolt-de Vries J, Meijer-van Gelder ME, van Putten WL, Klijn JG (1999) Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients. Br J Cancer 79:300–307PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Westley BR, May FE (1996) Cathepsin D and breast cancer. Eur J Cancer 32A:15–24PubMedCrossRefGoogle Scholar
  75. 75.
    Henry JA, McCarthy AL, Angus B, Westley BR, May FE, Nicholson S, Cairns J, Harris AL, Horne CH (1990) Prognostic significance of the estrogen-regulated protein, cathepsin D, in breast cancer. An immunohistochemical study. Cancer 65:265–271PubMedCrossRefGoogle Scholar
  76. 76.
    Kute TE, Shao ZM, Sugg NK, Long RT, Russell GB, Case LD (1992) Cathepsin D as a prognostic indicator for node-negative breast cancer patients using both immunoassays and enzymatic assays. Cancer Res 52:5198–5203PubMedGoogle Scholar
  77. 77.
    Isola J, Weitz S, Visakorpi T, Holli K, Shea R, Khabbaz N, Kallioniemi OP (1993) Cathepsin D expression detected by immunohistochemistry has independent prognostic value in axillary node-negative breast cancer. J Clin Oncol 11:36–43PubMedCrossRefGoogle Scholar
  78. 78.
    Ravdin PM, de Moor CA, Hilsenbeck SG, Samoszuk MK, Vendely PM, Clark GM (1997) Lack of prognostic value of cathepsin D levels for predicting short term outcomes of breast cancer patients. Cancer Lett 116:177–183PubMedCrossRefGoogle Scholar
  79. 79.
    Rothberg JM, Bailey KM, Wojtkowiak JW, Ben-Nun Y, Bogyo M, Weber E, Moin K, Blum G, Mattingly RR, Gillies RJ, Sloane BF (2013) Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia 15:1125–1137PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Withana NP, Blum G, Sameni M, Slaney C, Anbalagan A, Olive MB, Bidwell BN, Edgington L, Wang L, Moin K, Sloane BF, Anderson RL, Bogyo MS, Parker BS (2012) Cathepsin B inhibition limits bone metastasis in breast cancer. Cancer Res 72:1199–1209PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta 1824:68–88PubMedCrossRefGoogle Scholar
  82. 82.
    Tsukuba T, Okamoto K, Yasuda Y, Morikawa W, Nakanishi H, Yamamoto K (2000) New functional aspects of cathepsin D and cathepsin E. Mol Cells 10:601–611PubMedCrossRefGoogle Scholar
  83. 83.
    Coulibaly S, Schwihla H, Abrahamson M, Albini A, Cerni C, Clark JL, Ng KM, Katunuma N, Schlappack O, Glossl J, Mach L (1999) Modulation of invasive properties of murine squamous carcinoma cells by heterologous expression of cathepsin B and cystatin C. Int J Cancer 83:526–531PubMedCrossRefGoogle Scholar
  84. 84.
    Levicar N, Strojnik T, Kos J, Dewey RA, Pilkington GJ, Lah TT (2002) Lysosomal enzymes, cathepsins in brain tumour invasion. J Neurooncol 58:21–32PubMedCrossRefGoogle Scholar
  85. 85.
    Sadaghiani AM, Verhelst SH, Gocheva V, Hill K, Majerova E, Stinson S, Joyce JA, Bogyo M (2007) Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases. Chem Biol 14:499–511PubMedCrossRefGoogle Scholar
  86. 86.
    Parker BS, Ciocca DR, Bidwell BN, Gago FE, Fanelli MA, George J, Slavin JL, Moller A, Steel R, Pouliot N, Eckhardt B, Henderson MA, Anderson RL (2008) Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer. J Pathol 214:337–346PubMedCrossRefGoogle Scholar
  87. 87.
    Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, Bell-McGuinn KM, Zabor EC, Brogi E, Joyce JA (2011) Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25:2465–2479PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Minarowska A, Karwowska A, Gacko M (2009) Quantitative determination and localization of cathepsin D and its inhibitors. Folia Histochem Cytobiol 47:153–177PubMedCrossRefGoogle Scholar
  89. 89.
    Gacko M, Minarowska A, Karwowska A, Minarowski L (2007) Cathepsin D inhibitors. Folia Histochem Cytobiol 45:291–313PubMedGoogle Scholar
  90. 90.
    McConnell RM, Godwin WE, Sayyar K, Trana C, Green A, McConnell M, Young A, Young L, Hatfield SE (2005) Synthesis and evaluation of new cathepsin D Inhibitors. J Ark Acad Sci 59:122–131Google Scholar
  91. 91.
    Anantaraju HS, Battu MB, Viswanadha S, Sriram D, Yogeeswari P (2016) Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: molecular docking and bioevaluation against triple-negative and triple-positive breast cancers. Mol Divers 20:521–535PubMedCrossRefGoogle Scholar
  92. 92.
    Vezenkov LL, Sanchez CA, Bellet V, Martin V, Maynadier M, Bettache N, Lisowski V, Martinez J, Garcia M, Amblard M, Hernandez JF (2016) Structure-activity relationships of JMV4463, a vectorized cathepsin D inhibitor with antiproliferative properties: the unique role of the AMPA-based vector. Chem Med Chem 11:302–308PubMedCrossRefGoogle Scholar
  93. 93.
    Das SK, Menezes ME, Bhatia S, Wang XY, Emdad L, Sarkar D, Fisher PB (2015) Gene therapies for cancer: strategies, challenges and successes. J Cell Physiol 230:259–271PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Hizel C, Ferrara M, Cure H, Pezet D, Dechelotte P, Chipponi J, Rio P, Bignon YJ, Bernard-Gallon D (1998) Evaluation of the 5′ spliced form of human cathepsin B mRNA in colorectal mucosa and tumors. Oncol Rep 5:31–34PubMedGoogle Scholar
  95. 95.
    Gong Q, Chan SJ, Bajkowski AS, Steiner DF, Frankfater A (1993) Characterization of the cathepsin B gene and multiple mRNAs in human tissues: evidence for alternative splicing of cathepsin B pre-mRNA. DNA Cell Biol 12:299–309PubMedCrossRefGoogle Scholar
  96. 96.
    Krueger S, Haeckel C, Buehling F, Roessner A (1999) Inhibitory effects of antisense cathepsin B cDNA transfection on invasion and motility in a human osteosarcoma cell line. Cancer Res 59:6010–6014PubMedGoogle Scholar
  97. 97.
    Sokol JP, Schiemann WP (2004) Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol Cancer Res 2:183–195PubMedGoogle Scholar
  98. 98.
    Li W, Ding F, Zhang L, Liu Z, Wu Y, Luo A, Wu M, Wang M, Zhan Q, Liu Z (2005) Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis. Clin Cancer Res 11:8753–8762PubMedCrossRefGoogle Scholar
  99. 99.
    Vigneswaran N, Wu J, Nagaraj N, James R, Zeeuwen P, Zacharias W (2006) Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion. Life Sci 78:898–907PubMedCrossRefGoogle Scholar
  100. 100.
    Wang B, Sun J, Kitamoto S, Yang M, Grubb A, Chapman HA, Kalluri R, Shi GP (2006) Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J Biol Chem 281:6020–6029PubMedCrossRefGoogle Scholar
  101. 101.
    Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS (2004) RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene 23:8486–8496PubMedCrossRefGoogle Scholar
  102. 102.
    Gondi CS, Rao JS (2013) Cathepsin B as a cancer target. Expert Opin Ther Targets 17:281–291PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Glondu M, Liaudet-Coopman E, Derocq D, Platet N, Rochefort H, Garcia M (2002) Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells. Oncogene 21:5127–5134PubMedCrossRefGoogle Scholar
  104. 104.
    Vetvicka V, Benes P, Fusek M (2002) Procathepsin D in breast cancer: what do we know? Effects of ribozymes and other inhibitors. Cancer Gene Ther 9:854–863PubMedCrossRefGoogle Scholar
  105. 105.
    Fauvel B, Yasri A (2014) Antibodies directed against receptor tyrosine kinases: current and future strategies to fight cancer. MAbs 6:838–851PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Premzl A, Zavasnik-Bergant V, Turk V, Kos J (2003) Intracellular and extracellular cathepsin B facilitate invasion of MCF-10A neoT cells through reconstituted extracellular matrix in vitro. Exp Cell Res 283:206–214PubMedCrossRefGoogle Scholar
  107. 107.
    Reuning U, Sperl S, Kopitz C, Kessler H, Kruger A, Schmitt M, Magdolen V (2003) Urokinase-type plasminogen activator (uPA) and its receptor (uPAR): development of antagonists of uPA/uPAR interaction and their effects in vitro and in vivo. Curr Pharm Des 9:1529–1543PubMedCrossRefGoogle Scholar
  108. 108.
    Vetvicka V, Vetvickova J, Fusek M (1999) Anti-human procathepsin D activation peptide antibodies inhibit breast cancer development. Breast Cancer Res Treat 57:261–269PubMedCrossRefGoogle Scholar
  109. 109.
    Glondu M, Coopman P, Laurent-Matha V, Garcia M, Rochefort H, Liaudet-Coopman E (2001) A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells. Oncogene 20:6920–6929PubMedCrossRefGoogle Scholar
  110. 110.
    Vetvicka V (2012) Procathepsin D in cancer development. J Cancer Ther Res 1:22CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Biochemistry and Cancer BiologyMeharry Medical CollegeNashvilleUSA

Personalised recommendations