Matrix Metalloproteinases in Remodeling of the Normal and Neoplastic Mammary Gland

  • Laura A. Rudolph-Owen
  • Lynn M. Matrisian


Alterations in mammary gland structure andfunction are associated with changes in the expressionof members of the matrix metalloproteinase(MMP)3 family of enzymes. In this review, theevidence for a role for specific MMPs in mammary glanddevelopment and cellular differentiation, proliferation,and apoptosis is discussed. In addition, MMP expressionis altered during the development and progression of preneoplastic and neoplastic breast lesions.The expression of MMP family members in human breastcancer is described, and studies with mouse modelsystems addressing the role of MMPS in the initiation, growth, invasion, and metastasis of breastneoplasms are reviewed.



Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    H. Birkedal-Hansen (1995). Proteolytic remodeling of extracellular matrix. Curr. Opin. Cell Biol. 7: 728-735.Google Scholar
  2. 2.
    D. Q. Pei and S. J. Weiss (1996). Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity. J. Biol. Chem. 271: 9135-9140.Google Scholar
  3. 3.
    E. Ohuchi, K. Imai, Y. Fujii, H. Sato, M. Seiki, and Y. Okada (1997). Membrane type I matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 272: 2446-2451.Google Scholar
  4. 4.
    H. E. Van Wart and H. Birkedal-Hansen (1990). The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl. Acad. Sci. U.S.A. 87: 5578-5582.Google Scholar
  5. 5.
    J. Greene, M. Wang, Y. E. Liu, L. A. Raymond, C. Rosen, and Y. E. Shi (1996). Molecular cloning and characterization of human tissue inhibitor of metalloprotein ase 4. J. Biol. Chem. 271: 30375-30380.Google Scholar
  6. 6.
    C. Wolf, N. Rouyer, Y. Lutz, C. Adida, M. Loriot, J.-P. Bellocq, P. Chambon, and P. Basset (1993). Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibro-blastic cells and possibly implicated in tumor progression. Proc. Natl. Acad. Sci. U.S.A. 90: 1843-1847.Google Scholar
  7. 7.
    E. Hahnel, J. M. Harvey, R. Joyce, P. D. Robbins, G. F. Sterrett, and R. Hahnel (1993). Stromelysin-3 expression in breast cancer biopsies: Clinical-pathological correlations. Int. J. Cancer 55: 771-774.Google Scholar
  8. 8.
    J. M. P. Freije, I. Diez-Itza, M. Balbin, L. M. Sanchez, R. Blasco, J. Tolivia, and C. Lopez-Otin (1994). Molecular cloning and expression of collagenase-3, a novel human matrix metalloprotienase produced by breast carcinomas. J. Biol. Chem. 269: 16766-16773.Google Scholar
  9. 9.
    U. K. Saarialho-Kere, E. C. Crouch, and W. C. Parks (1995). The matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J. Invest. Dermatol. 105: 190-196.Google Scholar
  10. 10.
    C. Monteagudo, M. J. Merino, J. San-Juan, L. A. Liotta, and W. G. Stetler-Stevenson (1990). Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am. J. Pathol. 136: 585-592.Google Scholar
  11. 11.
    D. Medina (1996). The Mammary Gland: A unique organ for the study of development and tumorigenesis. J. Mam. Gland Biol. Neoplasia 1: 5-19.Google Scholar
  12. 12.
    J. P. Witty, J. Wright, and L. M. Matrisian (1995). Matrix metalloprotein ases are expressed during ductal and alveolar mammary morphogenesis, and misregulation of stromelysin-1 in transgenic mice induces unscheduled alveolar development. Mol. Biol. Cell 6: 1287-1303.Google Scholar
  13. 13.
    R. S. Talhouk, J. R. Chin, E. N. Unemori, Z. Werb, and M. J. Bissell (1991). Proteinases of the mammary gland: developmental regulation in vivo and vectorial secretion in culture. Development 112: 439-449.Google Scholar
  14. 14.
    C. J. Sympson, R. S. Talhouk, C. M. Alexander, J. R. Chin, S. M. Clift, M. J. Bissell, and Z. Werb (1994). Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J. Cell Biol. 125: 681-693.Google Scholar
  15. 15.
    A. Metcalfe and C. H. Streuli (1997). Epithelial apoptosis. BioEssays 19: 711-720.Google Scholar
  16. 16.
    R. S. Talhouk, M. J. Bissell, and Z. Werb (1992). Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J. Cell Biol. 118: 1271-1282.Google Scholar
  17. 17.
    S. R. Dickson and M. J. Warburton (1992). Enhanced synthesis of gelatinase and stromelysin by myoepithelial cells during involution of the rat mammary gland. J. Histochem. Cytochem. 40: 697-703.Google Scholar
  18. 18.
    F. Li, R. Strange, R. R. Friis, V. Djonov, H. Altermatt, S. Saurer, H. Niemann, and A. Andres (1994). Expression of stromelysin-1 and TIMP-1 in the involuting mammary gland and in early invasive tumors of the mouse. Int. J. Cancer 59: 560-568.Google Scholar
  19. 19.
    O. Lefebvre, C. Wolf, J.-M. Limacher, P. Hutin, C. Wendling, M. LeMeur, P. Basset, and M.-C. Rio (1992). The breast cancer-associated stromelysin-3 gene is expressed during mouse mammary gland apoptosis. J. Cell Biol. 119: 997-1002.Google Scholar
  20. 20.
    M. J. Warburton, E. J. Ormerod, P. Monaghan, S. A. Ferns, and P. S. Rudland (1981). Characterization of a myoepithelial cell line derived from a neonatal rat mammary gland. J. Cell Biol. 91: 827.Google Scholar
  21. 21.
    P. J. Keely, J. E. Wu, and S. A. Santoro (1995). The spatial and temporal expression of the α2β1 integrin and its ligands, collagen I, collagen IV, and laminin, suggest important roles in mouse mammary morphogenesis. Differentiation 59: 1-13.Google Scholar
  22. 22.
    L. M. Andersson, S. R. Dundas, M. J. O'Hare, B. A. Gusterson, and M. J. Warburton (1994). Synthesis of gelatinases by rat mammary epithelial and myoepithelial cell lines. Exp. Cell Res. 212: 389-392.Google Scholar
  23. 23.
    C. L. Wilson, K. J. Heppner, L. A. Rudolph, and L. M. Matrisian (1995). The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. Mol. Biol. Cell 6: 851-869.Google Scholar
  24. 24.
    S. R. Ross, C. L. L. Hsu, Y. Choi, E. Mok, and J. P. Dudley (1990). Negative regulation in correct tissue-specific expression of mouse mammary tumor virus in transgenic mice. Mol. Cell. Biol. 10: 5822-5829.Google Scholar
  25. 25.
    H. L. Nakhasi and P. K. Quasba (1979). Quantitation of milk proteins and their mRNAs in rat mammary gland at various stages of gestation and lactation. J. Biol. Chem. 254: 6016-6025.Google Scholar
  26. 26.
    C. L. Wilson and L. M. Matrisian (1996). Matrilysin: An epithelial matrix metalloproteinase with potentially novel functions. Int. J. Biochem. Cell Biol. 28: 123-136.Google Scholar
  27. 27.
    A. F. Chambers and L. M. Matrisian (1997). Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst. 89: 1260-1270.Google Scholar
  28. 28.
    G. W. Sledge, Jr, M. Qulali, R. Goulet, E. A. Bone, and R. Fife (1995). Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J. Natl. Cancer Inst. 87: 1546-1550.Google Scholar
  29. 29.
    S. A. Eccles, G. M. Box, W. J. Court, E. A. Bone, W. Thomas, and P. D. Brown (1996). Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res. 56: 2815-2822.Google Scholar
  30. 30.
    B. Davies, P. D. Brown, N. East, M. J. Crimmin, and F. R. Balkwill (1993). A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res. 53: 2087-2091.Google Scholar
  31. 31.
    J. R. MacDougall and L. M. Matrisian (1995). Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Metastasis Rev. 14: 351-362.Google Scholar
  32. 32.
    L. Ronnov-Jessen, O. W. Petersen, and M. Bissell (1996). Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiol. Rev. 76: 69-125.Google Scholar
  33. 33.
    A. Lochter and M. J. Bissell (1995). Involvement of extracellular matrix constituents in breast cancer. Sem. Cell Biol. 6: 165-173.Google Scholar
  34. 34.
    J. Strater, U. Wedding, T. F. Barth, K. Koretz, C. Elsing, and P. Moller (1996). Rapid onset of apoptosis in vitro follows disruption of beta 1 integrin/matrix interactions in human colonic crypt cells. Gastroenterology 110: 1776-1784.Google Scholar
  35. 35.
    S. M. Frisch and H. Francis (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124: 619-626.Google Scholar
  36. 36.
    N. Boudreau, C. J. Sympson, Z. Werb, and M. J. Bissell (1995). Suppression of interstitial collagenase and apoptosis in mammary epithelial cells by extracellular matrix. Science 267: 891-893.Google Scholar
  37. 37.
    S. Pullan, J. Wilson, A. Metcalfe, G. M. Edwards, N. Goberdhan, J. Tilly, J. A. Hickman, C. Dive, and C. H. Streuli (1996). Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J. Cell Sci. 109: 631-642.Google Scholar
  38. 38.
    J. P. Witty, T. Lempka, R. J. Coffey, Jr., and L. M. Matrisian (1995). Decreased tumor formation in 7,12-dimethyl benzanthracene-trea ted stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res. 55: 1401-1406.Google Scholar
  39. 39.
    C. M. Alexander, E. W. Howard, M. J. Bissell, and Z. Werb (1996). Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinase-1 transgene. J. Cell. Biol. 135: 1669-1677.Google Scholar
  40. 40.
    L. A. Rudolph-Owen, P. Cannon, and L. M. Matrisian (1998). The overexpression of the matrix metalloproteinase matrilysin results in premature mammary gland differentiation and male infertility. Mol. Biol. Cell 9: 421-435.Google Scholar
  41. 41.
    C. L. Wilson, K. J. Heppner, P. A. Labosky, B. L. M. Hogan, and L. M. Matrisian (1997). Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc. Natl. Acad.Sci. U.S.A. 94: 1402-1407.Google Scholar
  42. 42.
    P. Basset, J. P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J. M. Limacher, O. L. Podhajcer, M. P. Chenard, M. C. Rio, and P. Chambon (1990). A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348: 699-704.Google Scholar
  43. 43.
    G. Engel, K. Heselmeyer, G. Auer, M. Bäckdahl, E. Eriksson, and S. Linder (1994). Correlation between stromelysin-3 mRNA level and outcome of human breast cancer. Int. J. Cancer 58: 830-835.Google Scholar
  44. 44.
    P. Basset, C. Wolf, N. Rouyer, J.-P. Bellocq, M.-C. Rio, and P. Chambon (1994). Stromelysin-3 in stromal tissue as a control factor in breast cancer behavior. Cancer 74: 1045-1049.Google Scholar
  45. 45.
    E.-Hähnel, H. Dawkins, P. Robbins, and R. Hähnel (1994). Expression of stromelysin-3 and nm23 in breast carcinoma and related tissues. Int. J. Cancer 58: 157-160.Google Scholar
  46. 46.
    Y. Soini, T. Hurskainen, M. Höyhtyä, A. Oikarinen, and H. Autio-Harmainen (1994). 72 KD and 92 KD type IV collagenase, type IV collagen, and laminin mRNAs in breast cancer: A study by in situ hybridization. J. Histochem. Cytochem. 42: 945-951.Google Scholar
  47. 47.
    M. Polette, N. Gilbert, I. Stas, B. Nawrocki, A. Nöel, A. Remacle, W. G. Stetler-Stevenson, P. Birembaut, and M. Foidart (1994). Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy. Virchows Arch. Int. J. Pathol. 424: 641-645.Google Scholar
  48. 48.
    M. Polette, C. Clavel, M. Cockett, S. Girod de Bentzmann, G. Murphy, and P. Birembaut (1993). Detection and localization of mRNAs encoding matrix metalloproteinases and their tissue inhibitor in human breast pathology. Invasion Metastasis 13: 31-37.Google Scholar
  49. 49.
    K. Tryggvason, M. Höyhtyä, and C. Pyke (1993). Type IV collagenases in invasive tumors. Br. Cancer Res. Treat. 24: 209-218.Google Scholar
  50. 50.
    K. J. Heppner, L. M. Matrisian, R. A. Jensen, and W. H. Rodgers (1996). Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am. J. Pathol. 149: 273-282.Google Scholar
  51. 51.
    P. D. Brown, R. E. Bloxidge, E. Anderson, and A. Howell (1993). Expression of activated gelatinase in human invasive breast carcinoma. Clin. Exp. Metastasis 11: 183-189.Google Scholar
  52. 52.
    H. S. Azzam, G. A. Arand, M. E. Lippman, and E.W. Thompson (1993). Association of MMP-2 activation potential with metastatic progression in human breast cancer cell lines independent of MMP-2 production. J. Natl. Cancer Inst. 85: 1758-1764.Google Scholar
  53. 53.
    H. Kolkenbrock, A. Heckerkia, D. Orgel, N. Ulbrich, and H. Will (1997). Activation of progelatinase A and progelatinase A TIMP-2 complex by membrane type 2 matrix metalloproteinase. Biol. Chem. 378: 71-76.Google Scholar
  54. 54.
    H. Sato, T. Takino, V. Okada, J. Cao, A. Shinagawa, E. Yamamoto, and M. Seiki (1994). A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 370: 61-65.Google Scholar
  55. 55.
    A. Y. Strongin, B. L. Marmer, G. A. Grant, and G. I. Goldberg (1993) Plasma membrane-depen dent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J. Biol. Chem. 268: 14033-14039.Google Scholar
  56. 56.
    D. W. Visscher, M. Höyhtyä, S. K. Ottosen, C.-M. Liang, F. H. Sarkar, J. D. Crissman, and R. Fridman (1994). Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int. J. Cancer 59: 339-344.Google Scholar
  57. 57.
    H. Ueno, H. Nakamura, M. Inoue, K. Imai, M. Noguchi, H. Sato, M. Seiki, and Y. Okada (1997). Expression and tissue localization of membrane-types 1,2, and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res. 57: 2055-2060.Google Scholar
  58. 58.
    M. Polette, C. Gilles, V. Marchand, M. Seiki, J. M. Tournier, and P. Birembaut (1997). Induction of membrane-type matrix metalloproteinase 1 (MT1-MMP) expression in human fibroblasts by breast adenocarcinoma cells. Clin. Exp. Metastasis 15: 157-163.Google Scholar
  59. 59.
    H. Pulyaeva, J. Bueno, M. Polette, P. Birembaut, H. Sato, M. Seiki, and E. W. Thompson (1997). MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin. Exp. Metastasis 15: 111-20.Google Scholar
  60. 60.
    X. S. Puente, A. M. Pendas, E. Llano, G. Velasco, and C. Lopez-Otin (1996). Molcular cloning of a novel membrane-type matrix metalloprotein ase from a human breast carcinoma. Cancer Res. 56: 944-949.Google Scholar
  61. 61.
    C. Gilles, M. Polette, M. Seiki, P. Birembaut, and E.W. Thompson (1997). Implication of collagen type 1-induced membrane-type 1 matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab. Invest. 76: 651-660.Google Scholar
  62. 62.
    M. Wang, Y. E. Liu, J. Greene, S. Sheng, A. Fuchs, E. M. Rosen, and Y. E. Shi (1997). Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14: 2767-2774.Google Scholar
  63. 63.
    A. C. Noel, O. Lefebvre, E. Maquoi, L. Van Hoorde, M. P. Chenard, M. Mareel, J. M. Foidart, P. Basset, M. C. Rio, and L. Vanhoorde (1996). Stromelysin-3 expression promotes tumor take in nude mice. J. Clin. Invest. 97: 1924-1930.Google Scholar
  64. 64.
    A. Lochter, A. Srebrow, C. J. Sympson, N. Terracio, Z. Werb, and M. J. Bissell (1997). Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J. Biol. Chem. 272: 5007-5015.Google Scholar
  65. 65.
    M. D. Sternlicht, J. Xie, C. Sympson, M. Bissell, and Z. Werb (1997). Mice that express an autoactivating stromelysin-1 transgene develop progressive mammary gland lesions [Abstract]. Proc. Am. Ass. for Cancer Res. 38: 257.Google Scholar
  66. 66.
    L. A. Rudolph-Owen, R. Chan, W. J. Muller, and L. M. Matrisian (1998). The matrix metalloproteinase matrilysin accelerates mammary tumorigenesis. (submitted).Google Scholar
  67. 67.
    C. W. Daniel and G. B. Silberstein. (1987). The mammary gland development, regulation, and function. In M. C. Neville and C. W. Daniel (eds.), Development of the Rodent Mammary Gland Plenum Press, New York, pp. 3-36.Google Scholar
  68. 68.
    R. D. Cardiff (1984). Protoneoplasia: The molecular biology of murine mammary hyperplasia. Adv. Cancer Res 42: 167-190.Google Scholar
  69. 69.
    T. Yoneda, A. Sasaki, C. Dunstan, P. J. Williams, F. Bauss, Y. A. DeClerck, and G. R. Mundy (1997). Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J. Clin. Invest. 99: 2509-2517.Google Scholar
  70. 70.
    S. Koop, R. Khokha, E. E. Schmidt, I. C. MacDonald, V. L. Morris, A. F. Chambers, and A. C. Groom (1994). Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth Cancer Res 54: 4791-4797.Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Laura A. Rudolph-Owen
  • Lynn M. Matrisian

There are no affiliations available

Personalised recommendations