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Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: Mediated by the mannose-6-phosphate/IGF-II receptor?

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Abstract

The lysosomal protease Cathepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.

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References

  1. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK: SEER Cancer Statistics Review, 1973-1998, 2001

  2. Duffy MJ: The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis 10: 145–155, 1992

    Google Scholar 

  3. Spyratos F, Maudelonde T, Brouillet JP, Brunet M, Defrenne A, Andrieu C, Hacene K, Desplaces A, Rouesse J, Rochefort H: Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet 2: 1115–1118, 1989

    Google Scholar 

  4. Westley BR, May FE: Cathepsin D and breast cancer. Eur J Cancer 32A: 15–24, 1996

    Google Scholar 

  5. Rochefort H: Cathepsin D in breast cancer. Breast Cancer Res Treat 16: 3–13, 1990

    Google Scholar 

  6. Rochefort H, Garcia M, Glondu M, Laurent V, Liaudet E, Rey JM, Roger P: Cathepsin D in breast cancer: mechanisms and clinical applications, a 1999 overview. Clin Chim Acta 291: 157–170, 2000

    Google Scholar 

  7. Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H: Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res 49: 3904–3909, 1989

    Google Scholar 

  8. von Figura K, Hasilik A: Lysosomal enzymes and their receptors. Annu Rev Biochem 55: 167–193, 1986

    Google Scholar 

  9. Gieselmann V, Pohlmann R, Hasilik A, Von Figura K: Biosynthesis and transport of cathepsin D in cultured human fibroblasts. J Cell Biol 97: 1–5, 1983

    Google Scholar 

  10. Riley LB, Lange MK, Browne RJ, Cochrane PJ, Choi IJ, Davis B, Arcona S, Alhadeff JA: Analysis of cathepsin D in human breast cancer: usefulness of the processed 31 kDa active form of the enzyme as a prognostic indicator in node-negative and node-positive patients. Breast Cancer Res Treat 60: 173–179, 2000

    Google Scholar 

  11. Tedone T, Correale M, Barbarossa G, Casavola V, Paradiso A, Reshkin SJ: Release of the aspartyl protease cathepsin D is associated with and facilitates human breast cancer cell invasion. FASEB J 11: 785–792, 1997

    Google Scholar 

  12. Garcia M, Platet N, Liaudet E, Laurent V, Derocq D, Brouillet JP, Rochefort H: Biological and clinical significance of cathepsin D in breast cancer metastasis. Stem Cells 14: 642–650, 1996

    Google Scholar 

  13. Rochefort H, Capony F, Garcia M: Cathepsin D in breast cancer: from molecular and cellular biology to clinical applications. Cancer Cells 2: 383–388, 1990

    Google Scholar 

  14. Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 348: 1189–1196, 1996

    Google Scholar 

  15. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047–1059, 1997

    Google Scholar 

  16. Couissi D, Dubois V, Remacle C, Schonne E, Trouet A: Western immunoblotting and enzymatic activity analysis of cathepsin D in human breast cancer cell lines of different invasive potential. Regulation by 17beta-estradiol, tamoxifen and ICI 182,780. Clin Exp Metastasis 15: 349–360, 1997

    Google Scholar 

  17. Maudelonde T, Domergue J, Henquel C, Freiss G, Brouillet JP, Simony J, Pujol H, Rochefort H: Tamoxifen treatment increases the concentration of 52K-cathepsin D and its precursor in breast cancer tissue. Cancer 63: 1265–1270, 1989

    Google Scholar 

  18. Chalbos D, Philips A, Galtier F, Rochefort H: Synthetic antiestrogens modulate induction of pS2 and cathepsin-D messenger ribonucleic acid by growth factors and adenosine 3',5'-monophosphate in MCF7 cells. Endocrinology 133: 571–576, 1993

    Google Scholar 

  19. Westley B, May FE, Brown AM, Krust A, Chambon P, Lippman ME, Rochefort H: Effects of antiestrogens on the estrogen-regulated pS2 RNA and the 52-and 160-kiloDalton proteins in MCF7 cells and two tamoxifen-resistant sublines. J Biol Chem 259: 10030–10035, 1984

    Google Scholar 

  20. Westley B, Rochefort H: A secreted glycoprotein induced by estrogen in human breast cancer cell lines. Cell 20: 353–362, 1980

    Google Scholar 

  21. Barret AJ: Cathepsin D and other carboxyl proteinases. In: Proteases in Mammalian Cells and Tissue. Elsevier/North-Holland Biomedical Press, The Netherlands, 1977

    Google Scholar 

  22. Labarca C, Paigen K: A simple rapid and sensitive DNA assay procedure. Anal Biochem 102: 344–352, 1980

    Google Scholar 

  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–273, 1951

    Google Scholar 

  24. Leto G, Tumminello FM, Gebbia N, Rausa L: Kinetics of in vivo inhibition of tissue cathepsin D by pepstatin A. Int J Biochem 20: 917–920, 1988

    Google Scholar 

  25. Brunk UT, Dalen H, Roberg K, Hellquist HB: Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts. Free Radic Biol Med 23: 616–626, 1997

    Google Scholar 

  26. Schultz DC, Bazel S, Wright LM, Tucker S, Lange MK, Tachovsky T, Longo S, Niedbala S, Alhadeff JA: Western blotting and enzymatic activity analysis of cathepsin D in breast tissue and sera of patients with breast cancer and benign breast disease and of normal controls. Cancer Res 54: 48–54, 1994

    Google Scholar 

  27. Tannock IF, Rotin D: Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384, 1989

    Google Scholar 

  28. Martinez-Zaguilan R, Lynch RM, Martinez GM, Gillies RJ: Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. Am J Physiol 265(4Pt 1): C1015–C1029, 1993

    Google Scholar 

  29. Boyer MJ, Tannock IF: Regulation of intracellular pH in tumor cell lines: influence of microenvironmental conditions. Cancer Res 52: 4441–4447, 1992

    Google Scholar 

  30. Heuser J: Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH. J Cell Biol 108: 855–864, 1989

    Google Scholar 

  31. Kenessey A, Nacharaju P, Ko LW, Yen SH: Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration. J Neurochem 69: 2026–2038, 1997

    Google Scholar 

  32. Tandon AK, Clark GM, Chamness GC, Chirgwin JM, McGuire WL: Cathepsin D and prognosis in breast cancer. N Engl J Med 322: 297–302, 1990

    Google Scholar 

  33. Garvin S, Dabrosin C: Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Res 63: 8742–8748, 2003

    Google Scholar 

  34. Dabrosin C: Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle. J Clin Endocrinol Metab 88: 2695–2698, 2003

    Google Scholar 

  35. Dabrosin C, Margetts PJ, Gauldie J: Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Int J Cancer 107: 535–540, 2003

    Google Scholar 

  36. Dabrosin C, Hallstrom A, Ungerstedt U, Hammar M: Microdialysis of human breast tissue during the menstrual cycle. Clin Sci (Lond) 92: 493–496, 1997

    Google Scholar 

  37. Johnson MD, Westley BR, May FE: Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells. Br J Cancer 59: 727–738, 1989

    Google Scholar 

  38. Krishnan V, Wang X, Safe S: Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells. J Biol Chem 269: 15912–15917, 1994

    Google Scholar 

  39. Lorenzo K, Ton P, Clark JL, Coulibaly S, Mach L: Invasive properties of murine squamous carcinoma cells: secretion of matrix-degrading cathepsins is attributable to a deficiency in the mannose 6-phosphate/insulin-like growth factor II receptor. Cancer Res 60: 4070–4076, 2000

    Google Scholar 

  40. Mathieu M, Vignon F, Capony F, Rochefort H: Estradiol down-regulates the mannose-6-phosphate/insulin-like growth factor-II receptor gene and induces cathepsin-D in breast cancer cells: a receptor saturation mechanism to increase the secretion of lysosomal proenzymes. Mol Endocrinol 5: 815–822, 1991

    Google Scholar 

  41. Kornfeld S: Structure and function of the mannose 6-phosphate/insulin-like growth factor II receptors. Annu Rev Biochem 61: 307–330, 1992

    Google Scholar 

  42. De Souza AT, Yamada T, Mills JJ, Jirtle RL: Imprinted genes in liver carcinogenesis. FASEB J 11: 60–67, 1997

    Google Scholar 

  43. Hankins GR, De Souza AT, Bentley RC, Patel MR, Marks JR, Iglehart JD, Jirtle RL: M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12: 2003–2009, 1996

    Google Scholar 

  44. Lee JS, Weiss J, Martin JL, Scott CD: Increased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo. Int J Cancer 107: 564–570, 2003

    Google Scholar 

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Authors and Affiliations

  1. Division of Gynecologic Oncology, University Hospital, SE-581 85, Linköping, Sweden

    Charlotta Dabrosin

  2. Division of Pathology II, Faculty of Health Sciences, University Hospital, SE, Linköping, Sweden

    Ann-Charlotte Johansson & Karin Öllinger

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  1. Charlotta Dabrosin
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  2. Ann-Charlotte Johansson
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  3. Karin Öllinger
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Correspondence to Charlotta Dabrosin.

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Dabrosin, C., Johansson, AC. & Öllinger, K. Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: Mediated by the mannose-6-phosphate/IGF-II receptor?. Breast Cancer Res Treat 85, 229–238 (2004). https://doi.org/10.1023/B:BREA.0000025417.82291.36

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  • DOI: https://doi.org/10.1023/B:BREA.0000025417.82291.36

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