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Hormone resistance, invasiveness, and metastatic potential in breast cancer

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Summary

Critical phenotypic changes that occur during the progression of breast cancer include the loss of hormone-dependence, acquired resistance to systemic therapies, and increased metastatic potential. We have isolated a series of MCF-7 human breast cancer variants which exhibit hormone-independent growth, antiestrogen resistance, and increased metastatic potential. Analysis of the phenotypes of these variants strongly suggests that changes in the expression of specific genes may be critical to the generation of phenotypic diversity in the process of malignant progression in breast cancer. Epigenetic changes may contribute significantly to the generation of these phenotypic changes observed during breast cancer progression. Many of the characteristics of the progressed phenotypes appear to have arisen in response to appropriate selective pressures (growth in ovariectomized nude mice; growth in the presence of antiestrogens). These observations are consistent with the concept of clonal selection and expansion in the process of malignant progression.

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References

  1. Nevasoari K, Heikkinen M, Taskinen PJ: Tamoxifen and thrombosis. Lancet ii:946–947, 1978.

    Google Scholar 

  2. Enck RE, Rios CN: Tamoxifen treatment of metastatic breast cancer and antithrombin III levels. Cancer 53:2607–2609, 1984.

    PubMed  Google Scholar 

  3. Love RR: Tamoxifen therapy in primary breast cancer: biology, efficacy, and side effects. J Clin Oncol 7:803–815, 1989.

    PubMed  Google Scholar 

  4. Plotkin D, Lechner JJ, Jung WE, Rosen PJ: Tamoxifen flare in advanced breast cancer. J Am Med Assoc 240:2644–2646, 1978.

    Google Scholar 

  5. Clarysse A: Hormone-induced tumor flare. Eur J Cancer Clin Oncol 21:545–547, 1985.

    PubMed  Google Scholar 

  6. Engelsman E: Therapy of advanced breast cancer: a review. Eur J Cancer Clin Oncol 19:1775–1778, 1983.

    PubMed  Google Scholar 

  7. Legault-Poisson S, Jolivet J, Poisson R, Beretta-Piccoli M, Band PR: Tamoxifen-induced tumor stimulation and withdrawal response. Cancer Treat Rep 63:1839–1841, 1979.

    PubMed  Google Scholar 

  8. Magdelenat H, Pouillart P: Steroid hormone receptors in breast cancer.In Sheridan PJ, Blum K, Trachtenberg MC (eds) Steroid Receptors and Disease: Cancer Autoimmune, Bone and Circulatory Disorders. Marcel Dekker Inc., New York, 1988, pp 435–465.

    Google Scholar 

  9. McGuire WL, Clark GM: The prognostic role of progesterone receptor in human breast cancer. Semin Oncol 10:2–6, 1983.

    Google Scholar 

  10. Patterson JS, Edwards DG, Battersby LA: A review of the international clinical experience with tamoxifen. Jpn J Cancer Clinics, Suppl:157–183, 1981.

    Google Scholar 

  11. Vuletic L, Bugarski M, Boberic J, Milosauljevic A, Naumovic P: Treatment of advanced breast cancer with tamoxifen: a pilot study. Rev Endoc Related Cancer 9:533–545, 1981.

    Google Scholar 

  12. Litherland S, Jackson IM: Antioestrogens in the management of hormone-dependent cancer. Cancer Treat Rev 15:183–194, 1988.

    PubMed  Google Scholar 

  13. NATO: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Lancet ii:836–839, 1985.

    Google Scholar 

  14. BCT Committee: Adjuvant tamoxifen in the management of operable breast cancer: the Scottish trial. Lancet ii:171–175, 1987.

    Google Scholar 

  15. Brünner N, Clarke R, Lippman ME, Dickson RB: Models for studying the progression from hormone-dependency to independency in human breast cancer.In Lippman ME, Dickson RB (eds) Growth Regulation of Cancer, II. Alan R. Liss Inc, New York, 1990, pp 115–125.

    Google Scholar 

  16. Nowell PC: The clonal evolution of tumor cell populations. Science 194:23–28, 1976.

    PubMed  Google Scholar 

  17. Isaacs JT: Clonal heterogeneity in relation to response.In Stoll BA (ed) Endocrine Management of Cancer: Vol 1. Karger, Basel, 1988, pp 125–140.

    Google Scholar 

  18. Van Netten JP, Armstrong JB, Carlyle SS, Goodchild NL, Thornton IG, Brigden ML, Coy P, Fletcher C: Estrogen receptor distribution in the peripheral, intermediate and central regions of breast cancers. Eur J Cancer Clin Oncol 24:1885–1889, 1988.

    PubMed  Google Scholar 

  19. Leonessa F, Boulay V, Wright A, Thompson EW, Brünner N, Clarke R: The biology of breast tumor progression: acquisition of hormone-independence and resistance to cytotoxic drugs. Acta Oncol 31:115–123, 1991.

    Google Scholar 

  20. Clarke R, Lippman ME: Antiestrogen resistance: mechanisms and reversal.In Teicher BA (ed) Drug Resistance in Oncology. Marcel Dekker Inc., New York, 1992, pp 501–536.

    Google Scholar 

  21. Brünner N, Clarke R, Lippman ME, Dickson RB: Models for studying the progression from hormone-dependent to hormone-independent growth in human breast cancer.In Lippman ME, Dickson RB (eds) Growth Regulation of Cancer, II. Alan R. Liss, New York, 1990, pp 115–125.

    Google Scholar 

  22. Liotta LA, Rao CN, Wewer UM: Biochemical interactions of tumor cells with the basement membrane. Ann Rev Biochem 55:1037–1057, 1986.

    PubMed  Google Scholar 

  23. Liotta LA Rao CN, Barsky SH: Laminin receptors on human breast carcinoma: role in invasion of the extracellular matrix.In Rich MA, Hager JC, Furmanski P (eds) Understanding Breast Cancer. Marcel Dekker, New York, 1983, pp 87–97.

    Google Scholar 

  24. Castronovo V, Taraboletti G, Liotta LA, Sobel ME: Modulation of laminin receptor expression by estrogen and progestins in human breast cancer cell lines. J Natl Cancer Inst 81:781–788, 1989.

    PubMed  Google Scholar 

  25. Albini A, Graf J, Kitten GT, Kleinman HK, Martin GR, Veillette A, Lippman ME: 17β-estradiol regulates and V-Ha-ras transfection constitutively enhances MCF-7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci USA 83:8182–8186, 1986.

    PubMed  Google Scholar 

  26. Albini A, Aukerman SL, Ogle RC, Noonan DM, Fridman R, Martin G, Fidler IJ: The in vitro invasiveness and interactions with laminin of K-1735 melanoma cells. Evidence for laminin-binding affinities in high and low metastatic variants. Clin Exp Metastasis 7:437–451, 1989.

    PubMed  Google Scholar 

  27. Hunt G: The role of laminin in cancer invasion and metastasis. Exp Cell Biol 57:165–176, 1989.

    PubMed  Google Scholar 

  28. Fridman R, Scott AF, Muller D, Reich R, Penno MB: The role of cell adhesion and migration in the in vitro invasiveness of mouse adrenal carcinoma cells. Invasion Metastasis 10:208–224, 1990.

    PubMed  Google Scholar 

  29. Yamada KM, Akiyama SK, Hasegawa T, Hasegawa E, Humphries MJ: Recent advances in research on fibronectin and other cell attachment proteins. J Cell Biochem 28:79–97, 1985.

    PubMed  Google Scholar 

  30. Thompson EW, Reich R, Martin GR, Albini A: Factors regulating the basement membrane invasion by tumor cells.In Lippman ME, Dickson RB (eds) Breast Cancer: Cellular and Molecular Biology. Kluwer Academic Press, Boston, 1988, pp 239–249.

    Google Scholar 

  31. Werb Z, Mainardi CL, Vater CA, Harris ED: Endogenous activation of latent collagenase by rheumatoid synovial cells. N Engl J Med 296:1017–1023, 1977.

    PubMed  Google Scholar 

  32. Kao RT, Stern R: Collagenases in human breast carcinoma cell lines. Cancer Res 46:1349–1354, 1986.

    PubMed  Google Scholar 

  33. Thompson EW, Shima TB, Reich R, Graf J, Albini A, Martin GR, Dickson RB, Lippman ME: Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res 48:6764–6768, 1988.

    PubMed  Google Scholar 

  34. Reich R, Thompson EW, Iwamoto Y, Martin GR, Deason J, Fuller GC, Miskin R: Inhibitors of plasminogen activator, serine proteases and collagenase IV prevent invasion of basement membranes by metastatic cells. Cancer Res 48:3307–3312, 1988.

    PubMed  Google Scholar 

  35. Ossowski L, Reich E: Antibodies to plasminogen activator inhibit tumor metastasis. Cell 35:611–619, 1983.

    PubMed  Google Scholar 

  36. Mackay AR, Corbitt RH, Hartzler JL, Thorgeirsson UP: Basement membrane type IV collagenase degradation: evidence for the involvement of a proteolytic cascade independent of metalloproteinases. Cancer Res 50:5997–6001, 1990.

    PubMed  Google Scholar 

  37. Kao RT, Stern R: Elastases in human breast carcinoma cell lines. Cancer Res 46:1355–1358, 1986.

    PubMed  Google Scholar 

  38. Montcourrier P, Mangeat PH, Salazar G, Morisset M, Sahuquet A, Rochefort H: Cathepsin D in breast cancer cells can digest extracellular matrix in large acidic vesicles. Cancer Res 50:6045–6054, 1990.

    PubMed  Google Scholar 

  39. Petrova-Skalkova D, Krepela E, Rasnick D, Vicar J: A latent form of cathepsin B in pleural effusions. Biochem Med Metab Biol 38:219–227, 1987.

    PubMed  Google Scholar 

  40. Ryan TJ, Seeger JI, Kumar SA, Dickerman HW: Estradiol preferentially enhances extracellular tissue plasminogen activators of MCF-7 breast cancer cells. J Biol Chem 259:14324–14327, 1984.

    PubMed  Google Scholar 

  41. Cifone MA, Fidler IJ: Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA 78:6949–6952, 1981.

    PubMed  Google Scholar 

  42. Nicolson GL: Tumor cell instability, diversification and progression to the metastatic phenotype: from oncogene to oncofetal expression. Cancer Res 47:1473–1487, 1987.

    PubMed  Google Scholar 

  43. Clarke R, Dickson RB, Lippman ME: Hormonal aspects of breast cancer: growth factors, drugs and stromal interactions. CRC Crit Rev Oncol Hematol 12:1–23, 1992.

    Google Scholar 

  44. McLeskey SW, Honig SW, Gelmann EP, Zwiebel JA, Lippman ME, Kern FG: Estrogen dependence of a breast carcinoma cell line is overcome by transfection of a secreted fibroblast growth factor. J Cell Biochem suppl 16B:185, 1992.

    Google Scholar 

  45. McLeskey SW, Honig S, Lippman ME, Kern FG: MCF-7 cells transfected with an expression vector for fibroblast growth factor 4 exhibit opposite responses to tamoxifen in vivo and in vitro. Proc Am Assoc Cancer Res 33:269, 1992.

    Google Scholar 

  46. Nawata H, Chang MJ, Bronzert D, Lippman ME: Estradiol independent growth of a subline of MCF-7 human breast cancer cells in culture. J Biol Chem 256:6895–6902, 1981.

    PubMed  Google Scholar 

  47. Nawata H, Bronzert D, Lippman ME: Isolation and characterization of a tamoxifen resistant cell line derived from MCF-7 human breast cancer cells. J Biol Chem 256:5016–5021, 1981.

    PubMed  Google Scholar 

  48. van den Berg HW, Clarke R: Preliminary characterization of a tamoxifen resistant variant of the oestrogen responsive human breast cancer cell line ZR-75-1. Br J Cancer 52:421, 1985.

    Google Scholar 

  49. van den Berg HW, Lynch M, Martin J, Nelson J, Dickson GR, Crockard AD: Characterization of a tamoxifen-resistant variant of the ZR-75-1 human breast cancer cell line (ZR-75-9a1) and stability of the resistant phenotype. Br J Cancer 59:522–526, 1989.

    PubMed  Google Scholar 

  50. Bronzert DA, Greene GL, Lippman ME: Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology 117:1409–1417, 1985.

    PubMed  Google Scholar 

  51. Mullick A, Chambon P: Characterization of the estrogen receptor in two antiestrogen-resistant cell lines, LY2 and T47D. Cancer Res 50:333–338, 1990.

    PubMed  Google Scholar 

  52. Clarke R, Brünner N, Thompson EW, Glanz P, Katz D, Dickson RB, Lippman ME: The inter-relationships between ovarian-independent growth, antiestrogen resistance and invasiveness in the malignant progression of human breast cancer. J Endocrinol 122:331–340, 1989.

    PubMed  Google Scholar 

  53. Osborne CK, Coronado EB, Robinson JP: Human breast cancer in athymic nude mice: cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23:1189–1196, 1987.

    PubMed  Google Scholar 

  54. Gottardis MM, Jordan VC: Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48:5183–5187, 1988.

    PubMed  Google Scholar 

  55. Theillet C, Le Roy X, De Lapeyriere O, Grosgeorges J, Adnane J, Raynaud SD, Simony-Lafontaine J, Goldfarb M, Escot C, Birnbaum D, Gaudray P: Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas. Oncogene 4:915–922, 1989.

    PubMed  Google Scholar 

  56. Kern FG, Wellstein A, Flamm S, Zugmaier G, Cheville A, Lupu R, McLeskey S, Gelmann EP, Lippman ME: Secretion of heparin binding growth factors by breast cancer cells and their role in promoting cancer cell growth. Cancer Chemother 5:167–174, 1990.

    Google Scholar 

  57. Gomm JJ, Smith J, Ryall GK, Baillie R, Turnbull L, Coombes RC: Localization of basic fibroblast growth factor and transforming growth factor beta 1 in the human mammary gland. Cancer Res 51:4685–4692, 1991.

    PubMed  Google Scholar 

  58. Clarke R, Dickson RB, Brünner N: The process of malignant progression in human breast cancer. Ann Oncol 1:401–407, 1990.

    PubMed  Google Scholar 

  59. Clarke R, Brünner N, Katzenellenbogen BS, Thompson EW, Norman MJ, Koppi C, Paik S, Lippman ME, Dickson RB: Progression from hormone dependent to hormone independent growth in MCF-7 human breast cancer cells. Proc Natl Acad Sci USA 86:3649–3653, 1989.

    PubMed  Google Scholar 

  60. Brünner N, Boulay V, Fojo A, Freter C, Lippman ME, Clarke R: Acquisition of hormone-independence in MCF-7 cells is accompanied by increased expression of estrogen regulated genes but without DNA amplifications. Cancer Res, in press.

  61. Gottardis MM, Wagner RJ, Borden EC, Jordan VC: Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res 49:4765–4769, 1989.

    PubMed  Google Scholar 

  62. Fondo EY, Rosen PR, Fracchia AA, Urban JA: The problem of carcinoma developing in fibroadenoma. Cancer 43:563–567, 1979.

    PubMed  Google Scholar 

  63. Thompson EW, Brünner N, Torri J, Johnson MD, Boulay V, Wright A, Lippman ME, Steeg PS, Clarke R: The invasive and metastatic properties of hormone-independent and hormone-responsive variants of MCF-7 human breast cancer cells. Clin Exp Metastasis (in press).

  64. Ozzello L, Sordat M: Behavior of tumors produced by transplantation of human mammary cell lines in athymic nude mice. Eur J Cancer 16:553–559, 1980.

    PubMed  Google Scholar 

  65. Shafie SM, Liotta LA: Formation of metastasis by human carcinoma cells (MCF-7) in nude mice. Cancer Lett 11:81–87, 1981.

    Google Scholar 

  66. Price JE, Polyzos A, Zhang RD, Daniels LM: Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 50:717–721, 1990.

    PubMed  Google Scholar 

  67. Wiebe VJ, Osborne CK, McGuire WL, DeGregorio MW: Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol 10:990–994, 1992.

    PubMed  Google Scholar 

  68. Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M: Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83:1477–1482, 1991.

    PubMed  Google Scholar 

  69. Vignon F, Bouton MM, Rochefort H: Antiestrogens inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens. Biochem Biophys Res Commun 146:1502–1508, 1987.

    PubMed  Google Scholar 

  70. Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Derynck R, Dickson RB: Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48:417–428, 1987.

    PubMed  Google Scholar 

  71. Knabbe C, Kock A, Schmal M, Knust B, Dickson RB, Lippman ME, Voigt KD: Regulation of TGF-β1- and TGF-β2-expression in MCF-7 cells. Proc Am Assoc Cancer Res 32:208, 1991.

    Google Scholar 

  72. Bates SE, Davidson NHE, Valverius EM, Dickson RB, Freter CE, Tam JP, Kudlow JE, Lippman ME, Salomon S: Expression of transforming growth factor-α and its mRNA in human breast cancer: its regulation by estrogen and its possible functional significance. Mol Endocrinol 2:543–545, 1988.

    PubMed  Google Scholar 

  73. Read LD, Snider CE, Miller JS, Greene GL, Katzenellenbogen BS: Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines. Mol Endocrinol 2:263–271, 1988.

    PubMed  Google Scholar 

  74. Bae S-N, Arand G, Azzam H, Pavasant P, Torri J, Frandsen TL, Thompson EW: Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays. Breast Cancer Res Treat (this issue).

  75. Thompson EW, Katz D, Shima TB, Wakeling AE, Lippman ME, Dickson RB: ICI 164,384: a pure antagonist of estrogen-stimulated MCF-7 cell proliferation and invasiveness. Cancer Res 49:6929–6934, 1989.

    PubMed  Google Scholar 

  76. Wilhelm SM, Collier IE, Marmer BL, Essen AZ, Grant GA, Goldberg GI: SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem 263:6579–6587, 1988.

    PubMed  Google Scholar 

  77. Collier IE, Wilhelm SM, Eisen AZ, Marmer BL, Grant GA, Seltzer JL, Kronberger A, He C, Bauer E, Goldberg GI: H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem 263:6579–6587, 1988.

    PubMed  Google Scholar 

  78. Liotta LA: Tumor invasion and metastasis — role of the extracellular matrix. Cancer Res 46:1–7, 1986.

    PubMed  Google Scholar 

  79. Woessner JF: Matrix metalloproteinases and their inhibitors in tissue remodelling. FASEB J 5:2145–2154, 1991.

    PubMed  Google Scholar 

  80. Shi YE, Torri J, Sobel M, Yamada Y, Lippman ME, Dickson RB: Regulation of laminin receptors by progestin in T47D human breast cancer cells. Proc Am Assoc Cancer Res 32:66, 1991.

    Google Scholar 

  81. Thompson EW, Paik S, Brünner N, Sommers C, Zugmaier G, Clarke R, Shima TB, Torri J, Donahue S, Lippman ME, Martin GR, Dickson RB: Association of increased basement membrane-invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 150:534–544, 1992.

    PubMed  Google Scholar 

  82. Rubin H: Cancer development: the rise of epigenetics. Eur J Cancer 28:1–2, 1992.

    PubMed  Google Scholar 

  83. Nowell PC: Mechanisms of tumor progression. Cancer Res 46:2203–2207, 1986.

    PubMed  Google Scholar 

  84. Melchor JC, Rodriquez-Escudero FJ, Lujan S, Corcostegui B: Variation of estrogen and progesterone receptor status in breast cancer after tamoxifen therapy. Oncology 47:467–470, 1990.

    PubMed  Google Scholar 

  85. Pavlik EJ, Nelson K, Srinivasan S, Powell DE, Kenady DE, DePreist PD, Gallion HH, van Nagell JR: Resistance to tamoxifen with persisting sensitivity to estrogen: possible mediation by excessive antiestrogen binding site activity. Cancer Res 52:4106–4112, 1992.

    PubMed  Google Scholar 

  86. Pasqualini JR, Nguyen B-L: Estrone sulfatase activity and effect of antiestrogens on transformation of estrone sulfate in hormone-dependent vs independent human breast cancer cell lines. Breast Cancer Res Treat 18:93–98, 1991.

    PubMed  Google Scholar 

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Clarke, R., Thompson, E.W., Leonessa, F. et al. Hormone resistance, invasiveness, and metastatic potential in breast cancer. Breast Cancer Res Tr 24, 227–239 (1993). https://doi.org/10.1007/BF01833263

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