Early and Late Events in the Development of Human Breast Cancer

  • Helene S. Smith
  • Robert Stern
  • Edison Liu
  • Chris Benz
Part of the Basic Life Sciences book series (BLSC, volume 57)


There is a large body of literature using various model systems to address early events in neoplastic transformation. These studies (which encompass various suggested etiologic agents such as viruses, carcinogens, hormones and growth factors, oncogenes, radiation, etc.) all focus on the target cell itself. However, carcinomas arise in organized tissues where there is a close association with mesenchymal cells and their secreted products. Hence, it is reasonable to consider the possibility that abnormal stromal tissue may actively participate in some events of the malignant process. A number of recent studies suggest that this view may be particularly relevant for the induction of breast cancer. These studies provide evidence at the cellular and biochemical level that the fibroblasts obtained from breast cancer patients differ from those of normal women.


Breast Cancer Hyaluronic Acid Human Breast Cancer Skin Fibroblast Allelic Loss 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    B. Azzarone, M. Mareel, C. Billard, P. Scemama, C. Chaponnier, and A. Macieira-Coellho, Abnormal properties of skin fibroblasts from patients with breast cancer, Int. J. Cancer 33:759–764 (1984).PubMedCrossRefGoogle Scholar
  2. 2.
    S. L. Schor, A. M. Schor, P. Durning, and G. Rushton, Skin fibroblasts obtained from cancer patients display fetal-like migratory behavior on collagen gels, J. Cell Sci. 73:235–244 (1985).PubMedGoogle Scholar
  3. 3.
    P. Durning, S. L. Schor, and R. A. S. Sellwood, Fibroblasts from patients with breast cancer show abnormal migratory behavior in vitro, Lancet 890-892 (1984).Google Scholar
  4. 4.
    S. L. Schor, A. M. Schor, G. Rushton, and L. Smith, Adult fetal and transformed fibroblasts display different migratory phenotypes on collagen gels: Evidence for an isomorphic transition during fetal development, J. Cell Sci. 73:221–234 (1985).PubMedGoogle Scholar
  5. 5.
    E. F. Adams, C. J. Newton, H. Braunsberg, N. Shaikh, M. Ghilchik, and V. H. T. James, Effects of human breast fibroblasts on growth and 17β-estradiol dehydrogenase activity of MCF-7 cells in culture, Breast Cancer Res. and Treatment 11:165–172 (1988).CrossRefGoogle Scholar
  6. 6.
    B. P. Toole, Chapter 9, in: “Cell Biology of the Extracellular Matrix,” E. D. Hay, ed., Plenum Press, New York (1982).Google Scholar
  7. 7.
    E. A. Tourley, J. Torrance, Localization of hyaluronate and hyaluronate-binding protein on motile and non-motile fibroblasts, Exp. Cell Res. 161:17–28 (1984).CrossRefGoogle Scholar
  8. 8.
    B. P. Toole, G. Jackson, and J. Gross, Hyaluronate in morphogenesis: inhibition of chondrogenesis in vitro, Proc. Natl. Acad. Sci. USA 69:1384–1386 (1972).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Brecht, U. Mayer, E. Schlosser, and P. Prehm, Increased hyaluronate synthesis is required for fibroblast detachment and mitosis, Biochem. J. 239:445–450 (1986).PubMedGoogle Scholar
  10. 10.
    N. Mian, Analysis of cell-growth-phase-related variations in hyaluronate synthase activity of isolated plasma-membrane fractions of cultured human skin fibroblasts, Biochem. J. 237:333–342 (1986).PubMedGoogle Scholar
  11. 11.
    B. E. Lacy and C. B. Underhill, The hyaluronate receptor is associated with actin filaments, J. Cell Biol. 105:1394–1404 (1987).CrossRefGoogle Scholar
  12. 12.
    J. C. Angello, H. L. Hosick, and L. W. Anderson, Glycosaminoglycan synthesis by a cell line (C1-S1) established from a preneoplastic mouse mammary outgrowth, Cancer Res. 42:4975–4976 (1982).PubMedGoogle Scholar
  13. 13.
    B. P. Toole, C. Biswas, and J. Gross, Hyaluronate and invasiveness of the rabbit V2 carcinoma, Proc. Natl. Acad. Sci. USA 76:6299 (1979).PubMedCrossRefGoogle Scholar
  14. 14.
    K. Kimata, Y. Honma, M. Okayama, K. Oguri, M. Hozumi, and S. Suzuki, Increased synthesis of hyaluronic acid by mouse mammary carcinoma cell variants with high metastatic potential, Cancer Res. 43:1347–1354 (1983).PubMedGoogle Scholar
  15. 15.
    J. Tekauchi, M. Sobue, E. Sato, M. Shamoto, and K. Miura, Variation in glycosaminoglycan components of breast tumors, Cancer Res. 36:2133–2139 (1976).Google Scholar
  16. 16.
    G. Manley, and C. Warren, Serum hyaluronic acid in patients with disseminated neoplasm, J. Clin. Pathol. 40:626–630 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    A. B. Roberts, M. A. Anzano, L. C. Lamb, J. M. Smith, and M. B. Sporn, New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues, Proc. Natl. Acad. Sci. USA 78:5339–5343 (1981).PubMedCrossRefGoogle Scholar
  18. 18.
    C. Knabbe, M. E. Lippman, L. M. Wakefield, K. C. Flanders, A. Kasid, R. Derynck, and R. B. Dickson, Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells, Cell 48:417–428 (1987).PubMedCrossRefGoogle Scholar
  19. 19.
    R. B. Dickson, A. Kasid, K. K. Huff, S. E. Bates, C. Knabbe, D. Bronzert, E. P. Gelman, and M. E. Lippman, Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17β-estradiol or v-Ha-ras oncogene, Proc. Natl. Acad. Sci USA 84:837–841 (1987).PubMedCrossRefGoogle Scholar
  20. 20.
    R. A. Ignotz and J. Massagué, Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix, J. Biol. Chem. 261:4337–4345 (1986).PubMedGoogle Scholar
  21. 21.
    J. Massagué, S. Cheifetz, T. Endo, and B. Nadel-Ginard, Type β transforming growth factor is an inhibitor of myogenic differentiation, Proc. Natl. Acad. Sci. USA 83:8206–8210 (1986).PubMedCrossRefGoogle Scholar
  22. 22.
    A. B. Roberts, M. B. Sporn, R. K. Assoian, J. M. Smith, N. S. Roche, L. M. Wakefield, U. I. Heine, L. A. Liotta, V. Falanga, J. H. Kehrl, and A. S. Fanci, Transforming growth factor type β: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro, Proc. Natl. Acad. Sci. USA 83:4167–4171 (1986).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Bassols, and J. Massagué, Transforming growth factor type β specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells, Proc. Natl. Acad. Sci. USA 84:5287–5291 (1987).CrossRefGoogle Scholar
  24. 24.
    J.-K. Chen, H. Hoshi, and W. L. McKeehan, Transforming growth factor type β specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells, Proc. Natl. Acad. Sci. USA 84:5287–5291 (1987).PubMedCrossRefGoogle Scholar
  25. 25.
    R. A. Ignotz and J. Massagué, cell adhesion protein receptors as targets for transforming growth factors-β action, Cell 51:189–197 (1987).PubMedCrossRefGoogle Scholar
  26. 26.
    R. Stern, J. T. Huey, J. Hall, and H. S. Smith, Hyaluronic acid production in response to type-β transforming growth factor distinguishes normal from breast cancer-derived fibroblasts, submitted for publication.Google Scholar
  27. 27.
    W. Wharton, Newborn human skin fibroblasts senesce in vitro without acquiring adult growth factor requirements, Exp. Cell Res. 154:310 (1984).PubMedCrossRefGoogle Scholar
  28. 28.
    W. Schurch, T. A. Seemayer, and R. Lagace, Stromal myofibroblasts in primary invasive and metastatic carcinomas, Virchows Arch. (Pathol. Anat.) a391:125–139 (1981).CrossRefGoogle Scholar
  29. 29.
    S. H. Barsky, W. R. Green, G. R. Grotendorst, and L. Liotta, Desmoplastic breast carcinoma as a source of human myofibroblasts, Am. J. Pathol. 115:329–333 (1983).Google Scholar
  30. 30.
    B. A. Gusterson, M. J. Warbutron, D. Mitchell, M. Ellison, A. M. Neville, and P. S. Rudland, Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases, Cancer Res. 42:4763–4770 (1982).PubMedGoogle Scholar
  31. 31.
    A.-P. Sappino, O. Skalli, B. Jackson, W. Schurch, and B. Gabbiani, Smooth muscle differentiation in stromal cell of malignant and non-malignant breast tissues, Int. J. Cancer 41:707–712 (1988).PubMedCrossRefGoogle Scholar
  32. 32.
    A. van den Hooff, The part played by the stroma in carcinogenesis, Perspec. Biol. 27:498 (1984).Google Scholar
  33. 33.
    D. J. Slamon, G. M. Clark, S. J. Wong, W. J. Levin, A. Ullrich, and W. L. McGuire, Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene, Science 235:177–182 (1987).PubMedCrossRefGoogle Scholar
  34. 34.
    M. van de Vijver, R. Van de Berssalaar, P. Deville, C. Cornelisse, J. Peterse, and R. Nusse, Amplification of the neu (c-erbB-2) oncogene in human mammary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene, Mol. Cell. Biol. 7:2019–2023 (1987).PubMedGoogle Scholar
  35. 35.
    C. Theillet, R. Lidereau, C. Escot, P. Hutzell, M. Brunet, J. Gest, J. Schlom, and R. Callahan, Loss of a c-Ha-ras-1 allele and aggressive human primary breast carcinoma, Cancer Res. 46:4776–4781 (1986).PubMedGoogle Scholar
  36. 36.
    M. J. Cline, H. Battifora, J. Yokota, Proto-oncogene abnormalities in human breast cancer: with anatomic features and clinical course of disease, J. Clin. Oncology 5:999–1006 (1987).Google Scholar
  37. 37.
    C. Escot, C. Theillet, R. Ledereau, F. Spyratos, M.-H. Champeme, J. Gest, and R. Callahan, Genetic alteration of the c-myc proto-oncogene (MYC) in human primary breast carcinoma, Proc. Natl. Acad. Sci. USA 83:4834–4838 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    M. H. Kraus, Y. Yuasa, and S. A. Aaronson, A position 12-activated Ha-ras oncogene in all HS578T mammary careinosarcoma cells but not normal mammary cells of the same patient, Proc. Natl. Acad. Sci. USA 81:5384 (1984).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Zarbl, S. Sukumar, A. V. Arthur, D. Martin-Zanca, and M. Barbacid, Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats, Nature 315:382–385 (1985).PubMedCrossRefGoogle Scholar
  40. 40.
    M. Barbacid, ras genes, Ann. Rev. Biochem. 56:779–827 (1987).PubMedCrossRefGoogle Scholar
  41. 41.
    S. Rodenhuis, M. L. van de Wetering, W. J. Moot, S. G. Evers, N. van Zandwizh, J. L. Bos, Mutational activation of the K-ras oncogene: A possible pathogenetic factor in adenocarcinoma of the lung, N. Eng. J. Med. 317:929–935 (1987).CrossRefGoogle Scholar
  42. 42.
    J. L. Bos, E. R. Feron, S. R. Hamilton, M. Verlaan-de Veries, J. H. van Boom, A. J. van der Eb, B. Vogelstein, Prevalence of ras gene mutations in human colorectal cancers, Nature 327:293–297 (1987).PubMedCrossRefGoogle Scholar
  43. 43.
    K. Forrester, C. Almoquera, K. Han, W. E. Gizzle, and M. Perucho, Detection of high incidence of K-ras oncogenes during human colon tumorigenesis, Nature 327:298–303 (1987).PubMedCrossRefGoogle Scholar
  44. 44.
    J. L. Bos, D. Toksoz, C. J. Marshall, M. Verlaan-de Veries, Amino acid substitutions in codon 13 of the N-ras oncogene in human acute myeloid leukemia, Nature 315:726–730 (1985).PubMedCrossRefGoogle Scholar
  45. 45.
    J. L. Bos, M. Verlaan-de Veries, A. J. van der Eb, J. W. G. Janssen, R. Delwel, B. Lowenberg and L. P. Colby, Mutations in N-ras predominate in acute myeloid leukemia, Blood 69:1237–1241 (1987).PubMedGoogle Scholar
  46. 46.
    M. T. Prosperi, J. Even, F. Calvo, J. Lebeau, and G. Goubin, Two adjacent mutations at position 12 activate the K-ras-2 oncogene in a human mammary tumor cell line, Qncogene Res. 1:121 (1987).Google Scholar
  47. 47.
    S. C. Kozma, M. E. Bogaard, K. Buser, S. M. Saurer, J. L. Bos, B. Groner, and N. E. Hynes, The human c-Kirsten ras gene is activated by a novel mutation in codon 13 in the breast carcinoma cell line MDA-MB231, Nucl. Acid Res. 15:5963–5971 (1987).CrossRefGoogle Scholar
  48. 48.
    C. F. Rochlitz, G. K. Scott, J. M. Dodson, E. Liu, C. Dollbaum, H. S. Smith, and C. C. Benz, Incidence of activated ras oncogene mutations associated with primary and metastatic human breast cancer, Cancer Res. 49:357–360 (1989).PubMedGoogle Scholar
  49. 49.
    E. Liu, C. Dollbaum, G. Scott, C. Rochlitz, C. Benz, and H. S. Smith, Molecular lesions involved in the progression of a human breast cancer, Oncogene 3:323–327 (1988).PubMedGoogle Scholar
  50. 50.
    H. S. Smith, S. R. Wolman, S. H. Dairkee, M. C. Hancock, M. Lippman, A. Leff, and A. J. Hackett, Immortalization in culture: occurrence at a late stage in progression of breast cancer, J. Natl. Cancer Inst. 78:611–615 (1987).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Helene S. Smith
    • 1
  • Robert Stern
    • 2
  • Edison Liu
    • 3
  • Chris Benz
    • 4
  1. 1.Peralta Cancer Research InstituteOaklandUSA
  2. 2.Department of PathologyUniversity of California, School of MedicineSan FranciscoUSA
  3. 3.Lineburger Cancer Research CenterUniversity of North Carolina, School of MedicineChapel HillUSA
  4. 4.Cancer Research InstituteUniversity of California, School of MedicineSan FranciscoUSA

Personalised recommendations