The role of metalloproteinases and their inhibitors in regulating mammary epithelial morphology and function in vivo

Summary

An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of the BM during mammary gland development in vivo, we generated transgenic mice which inappropriately express autoactivating isoforms of the matrix metalloproteinase, stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. The mammary glands from virgin transgenic mice had supernumerary branches and showed precocious development of alveoli that expressed β-casein. During midpregnancy, the alveolar structures were collapsed and mouse mammary epithelial cells underwent apoptosis. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of SL-1 and disruption of the BM may play a key role in mammary gland branching morphogenesis, apoptosis and breast cancer induction and progression.

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References

  1. 1

    Alexander, C.M. and Werb, Z., In Hay, E.D. (Ed.) Cell Biology of the Extracellular Matrix, Plenum Press, New York, NY, 1991, pp. 255–302.

    Google Scholar 

  2. 2

    Matrisian, L.M., Trends Genet., 6 (1990) 121.

    Google Scholar 

  3. 3

    Danø, K., Andreasen, P.A., Grøndahl-Hansen, J., Kristensen, B., Nielsen, L.S. and Skriver, L., Adv. Cancer Res., 44 (1985) 146.

    Google Scholar 

  4. 4

    Murphy, G.J.P., Murphy, G. and Reynolds, J.J., FEBS Lett., 289 (1991) 4.

    Google Scholar 

  5. 5

    McDonnell, S. and Matrisian, L.M., Cancer Metastasis Rev., 9 (1990) 302.

    Google Scholar 

  6. 6

    Leco, K.J., Khokha, R., Pavloff, N., Hawkes, S.P. and Edwards, D.R., J. Biol. Chem., 269 (1994) 9352.

    Google Scholar 

  7. 7

    Talhouk, R.S., Bissell, M.J. and Werb, Z., J. Cell Biol., 118 (1992) 1271.

    Google Scholar 

  8. 8

    Sympson, C.J., Talhouk, R.S., Alexander, C.M., Chin, J.R., Clift, S.M., Bissell, M.J. and Werb, Z., J. Cell Biol., 125 (1994) 681.

    Google Scholar 

  9. 9

    Boudreau, N., Sympson, C.J., Werb, Z. and Bissell, M.J., Science, 267 (1995) 891.

    Google Scholar 

  10. 10

    Sympson, C.J., Thomasset, N., Alexander, C.M., Bissell, M.J. and Werb, Z., Mol. Biol. Cell, 5 (1994) 428a.

    Google Scholar 

  11. 11

    Talhouk, R.S., Chin, J.R., Unemori, E.N., Werb, Z. and Bissell, M.J., Development, 112 (1991) 439.

    Google Scholar 

  12. 12

    Thomasset, N., Sympson, C.J., Lund, L., Bissell, M.J. and Werb, Z., Mol. Biol. Cell, 5 (1994) 181a.

    Google Scholar 

  13. 13

    Knight, C.H. and Peaker, M., J. Reprod. Fertil., 65 (1982) 521.

    Google Scholar 

  14. 14

    Daniel, C.W. and Silberstein, G.B., In Neville, M.C. and Daniel, C.W. (Eds.) The Mammary Gland: Development, Regulation and Function, Plenum Press, New York, NY, 1987, pp. 3–36.

    Google Scholar 

  15. 15

    Forsyth, I.A., Bailliere's Clin. Endocrinol. Metab., 5 (1991) 809.

    Google Scholar 

  16. 16

    Aggeler, J., Ward, J., Mackenzie-Blackie, L., Barcellos-Hoff, M.H., Streuli, C.H. and Bissell, M.J., J. Cell Sci., 99 (1991) 407.

    Google Scholar 

  17. 17

    Parry, G., Cullen, B., Kaetzel, S., Dramer, R. and Moss, L., J. Cell Biol., 105 (1987) 2043.

    Google Scholar 

  18. 18

    Barcellos-Hoff, M.H., Aggeler, J., Ram, T.G. and Bissell, M.J., Development, 105 (1989) 223.

    Google Scholar 

  19. 19

    Martinez-Hernandez, A., Fink, L.M. and Pierce, G.B., Lab. Invest., 31 (1976) 455.

    Google Scholar 

  20. 20

    Ossowski, L., Biegel, D. and Reich, E., Cell, 16 (1979) 929.

    Google Scholar 

  21. 21

    Strange, R., Li, F., Saurer, S., Burkhardt, A. and Friis, R.R., Development, 115 (1992) 49.

    Google Scholar 

  22. 22

    Walker, N.I., Bennett, R.E. and Kerr, J.F., Am. J. Anat., 185 (1989) 19.

    Google Scholar 

  23. 23

    Wolf, C., Chenard, M.-P., Durand de Grossouvre, P., Bellocq, J.-P., Chambon, P. and Basset, P., J. Invest. Dermatol., 99 (1992) 870.

    Google Scholar 

  24. 24

    Chin, J.R., Murphy, G. and Werb, Z., J. Biol. Chem., 260 (1985) 45.

    Google Scholar 

  25. 25

    Sanchez-Lopez, R., Nicholson, R., Gesnel, M.C., Matrisian, L.M. and Breathnach, R., J. Biol. Chem., 263 (1988) 11892.

    Google Scholar 

  26. 26

    Mignatti, P. and Rifkin, D.B., Physiol. Rev., 73 (1993) 161.

    Google Scholar 

  27. 27

    Hurley, W.L., J. Dairy Sci., 72 (1989) 1637.

    Google Scholar 

  28. 28

    Monteagudo, C., Merino, M.J., San-Juan, J., Liotta, L.A. and Stetler-Stevenson, W.G., Am. J. Pathol., 136 (1990) 585.

    Google Scholar 

  29. 29

    Wicha, M.S., Liotta, L.A., Vonderhaar, B.K. and Kidwell, W.R., Dev. Biol., 80 (1980) 253.

    Google Scholar 

  30. 30

    Steller, H., Science, 267 (1995) 1445.

    PubMed  Google Scholar 

  31. 31

    Sympson, C.J., Alexander, C.M., Howard, E., Talhouk, R.S., Werb, Z. and Bissell, M.J., Mol. Biol. Cell, 5 (1994) 429a.

    Google Scholar 

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Correspondence to Zena Werb.

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Sympson, C.J., Talhouk, R.S., Bissell, M.J. et al. The role of metalloproteinases and their inhibitors in regulating mammary epithelial morphology and function in vivo. Perspectives in Drug Discovery and Design 2, 401–411 (1995). https://doi.org/10.1007/BF02172033

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Key words

  • ECM
  • Proteinases
  • Mammary gland
  • Apoptosis
  • Breast cancer