Growth factor and sex steroid interactions in breast cancer

  • Nicholas J. Kenney
  • Robert B. Dickson


Mitogenic and inhibitory growth factors and steroid ovarian hormones play important roles as selective modulators of normal mammary development and in the onset and the progression of human breast cancer. The focus of this article is to review past and current research on the interactions of these two classes of effectors in mammary gland development and neoplasia. Steroid hormones regulate synthesis of growth stimulatory and inhibitory growth factors, growth factor receptors, and growth factor binding proteins. In turn, growth factor pathways may modulate phosphorylation and function of steroid receptors and potentiate or inhibit the mitogenic actions of steroids. Ultimately, during the progression of the malignant mammary epithelial cell to hormonal autonomy, overexpression, mutation, or disregulation of key elements of growth factor signal transduction pathways all may play critical roles.

Key words

Autocrine paracrine endocrine morphogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    C. W. Daniel and G. B. Silberstein (1987). Postnatal development of the rodent mammary gland. In M. C. Neville and C. W. Daniel (eds.),The Mammary Gland: Development, Regulation, and Function, Plenum Press, New York, pp. 3–36.Google Scholar
  2. 2.
    N. Kenney, H. Hosick, G. Herrington, and G. H. Smith (1995). The aged mouse mammary gland. In G. Duagworth (ed.),The Pathobiology of the Aging Mouse, ICSI Press, Hanover, Germany (in press).Google Scholar
  3. 3.
    S. A. Pringent and N. R. Lemoine (1992). The type-1 (EGFR-related) family of growth factor receptors and their ligands.Prog. Growth Factor Res. 4:1–24.PubMedGoogle Scholar
  4. 4.
    N. Hynes (1996). ErbB2 activation and signal transduction in normal and malignant mammary cells.J. Mam. Gland Biol. Neoplasia 1(2):199–206.Google Scholar
  5. 5.
    S. Coleman, G. B. Silberstein, and C. W. Daniel (1988). Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor.Dev. Biol. 127:304–315.PubMedGoogle Scholar
  6. 6.
    R. B. Dickson and M. E. Lippman (1991). Growth regulation of normal and malignant breast epithelium. In K. I. Bland and E. M. Copeland (eds.),The Breast, W.B. Saunders, Philadelphia, pp. 363–394.Google Scholar
  7. 7.
    S. M. Snedeker, C. Brown, and R. P. DiAugustine (1991). Expression and functional properties of transforming growth factor α and epidermal growth factor during mouse mammary gland ductal morphogenesis.Proc. Natl. Acad. Sci. U.S.A. 88:276–280.PubMedGoogle Scholar
  8. 8.
    D. S. Salomon, R. B. Dickson, N. Normanno, T. Saeki, N. Kim, N. Kenney, and F. Ciardiello (1992). Interaction of oncogenes and growth factors in colon and breast cancer. In D. A. Spandidos (ed.),Current Perspectives on Molecular and Cellular Oncology, London, JAI Press Ltd., pp. 211–261.Google Scholar
  9. 9.
    D. M. Parham and J. Jankowski (1992). Transforming growth factor α in epithelial proliferative diseases of the breast.J. Clin. Pathol. 45:513–516.PubMedGoogle Scholar
  10. 10.
    B. K. Vonderhaar (1993). Local effects of cholesterol carrier system on binding of lactogens and epidermal growth factor to the developing mammary gland.Endocrinology 133:427–429.PubMedGoogle Scholar
  11. 11.
    C. Jhappan, C. Stahle, R. N. Harkins, N. Fausto, G. H. Smith, and G. T. Merlino (1990). TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.Cell 61:1137–1146.PubMedGoogle Scholar
  12. 12.
    E. P. Sandgren, N. C. Luetteke, R. D. Palmiter, R. L. Brinster, and D. C. Lee (1990). Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast.Cell 61:1121–1135.PubMedGoogle Scholar
  13. 13.
    M. Shoyab, U. L. McDonald, J. G. Bradley, and G. J. Todero (1988). Amphiregulin: a bi-functional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7.Proc. Natl. Acad. Sci. U.S.A. 85:6528–6532.PubMedGoogle Scholar
  14. 14.
    N. J. Kenney, R. Huang, G. Johnson, D. Okamura, W. Matheny, G. Plowman, G. H. Smith, D. S. Salomon, and E. D. Adamson (1995). Detection and location of amphiregulin and cripto-1 in the developing mouse mammary gland.Mol. Reprod. Dev. 41:277–286.PubMedGoogle Scholar
  15. 15.
    N. Kenney, G. Johnson, M. P. Selwin, N. King, C. Qi, T. Saeki, R. Brandt, B. Jones, F. Ciardiello, M. Shoyab, G. Plowman, A. Day, D. S. Salomon, and N. Normanno (1993). Transforming growth factor (TGFα) and amphiregulin (AR) as autocrine growth factors in non-transformed, immortalized 184A1N4 human mammary epithelial cells.Mol. Cell. Diff. 1:163–184.Google Scholar
  16. 16.
    N. J. Kenney, G. H. Smith, and R. B. Dickson (1995). Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland (submitted).Google Scholar
  17. 17.
    N. J. Kenney, G. H. Smith, W. J. Muller, J. Green, R. H. Callahan, D. S. Salomon, and R. B. Dickson (1995). Detection of amphiregulin and cripto-1 in mammary tumors from transgenic mice.Mol. Carcinog. (in press).Google Scholar
  18. 18.
    A. Ciccodicola, R. Dono, S. Obici, A. Simeone, M. Zollo, and M. G. Persico (1989). Molecular characterization of a gene of the EGF family expressed in undifferentiated human NTERA2 teratocarcinoma cells.EMBO 8:1987–1991.Google Scholar
  19. 19.
    R. Brandt, N. Normanno, W. J. Gullick, R. Harkins, D. Scheider, B. Jones, F. Ciardiello, N. Kim, and D. S. Salomon (1994). Physiochemical and biological characterization of human cripto-1: a novel epidermal growth factor-related protein.J. Biol. Chem. 269:17320–17328.PubMedGoogle Scholar
  20. 20.
    N. Kenney (submitted).Google Scholar
  21. 21.
    G. H. Smith, R. Sharp, E. Kordon, C. Jhappan, and G. Merlino (1995). Transforming growth factor a promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells.Am. J. Pathol. (in press).Google Scholar
  22. 22.
    G. R. Merlo, F. Basolo, L Duboc, and N. E. Hynes (1995). p53-dependent and p53 independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin.J. Cell Biol. 128:1185–1196.PubMedGoogle Scholar
  23. 23.
    R. B. Dickson and M. E. Lippman (1995). Growth factors and breast cancerEndocrine Rev. 16:559–589.Google Scholar
  24. 24.
    S. D. Robinson, G. B. Silberstein, A. B. Roberts, K. C. Flanders, and C. W. Daniel (1991). Regulated expression and growth inhibitory effects of transforming growth factor-b-isoforms in mouse mammary gland development.Development 113:867–878.PubMedGoogle Scholar
  25. 25.
    G. B. Silberstein and C. W. Daniel (1987). Reversible inhibition of mammary gland growth by transforming growth factor-β.Science 237:291–293.PubMedGoogle Scholar
  26. 26.
    E. C. Kordon, R. A. McKnight, C. Jhappan, L. Hennighausen, G. Merlino, and G. H. Smith (1995). Ectopic TGFβ1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population.Dev. Biol. 168:47–61.PubMedGoogle Scholar
  27. 27.
    C. Knabbe, L. Wakefield, K. Flanders, A. Kasid, R. Derynck, M. E. Lippman, and R. B. Dickson (1987). Evidence that TGF beta is a hormonally regulated negative growth factor in human breast cancer.Cell 48:417–428.PubMedGoogle Scholar
  28. 28.
    M. R. Stampfer, P. Yaswen, M. Alhadeff, and J. Hosoda (1993). TGFβ induction of extracellular matrix associated proteins in normal and transformed human mammary epithelial cells in culture is independent of growth effects.J. Cell Physiol. 155:210–221.PubMedGoogle Scholar
  29. 29.
    C. L. Artega, A. K. Tandon, D. D. Von Hoff, and C. K. Osborne (1988). Transforming growth factor β: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells.Cancer Res. 48:3898–3904.PubMedGoogle Scholar
  30. 30.
    J. Massague (1992). Receptors for the TGFβ family.Cell 69:1067–1070.PubMedGoogle Scholar
  31. 31.
    L. S. Mathews (1994). Activin receptors and cellular signaling by the receptor serine kinase family.Endocrine Rev. 15:310–325.Google Scholar
  32. 32.
    T. Wang, P. K. Donahoe, and A. S. Zervos (1994). Specific interaction of type I receptors of the TGFβ family with the immunophilin FKBP-12.Science 265:674–676.PubMedGoogle Scholar
  33. 33.
    S. M. Gorsch (1992). Immunohistochemical staining for transforming growth factor beta associates with disease progression in human breast cancer.Cancer Res. 52:6949–6952.PubMedGoogle Scholar
  34. 34.
    C. L. Arteaga, T. Carty-Dugger, H. L. Moses, S. D. Hurd, and J. A. Pietenpol (1993). Transforming growth factor β1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice.Cell Growth Diff. 4:193–201.PubMedGoogle Scholar
  35. 35.
    C. W. Daniel, G. B. Silberstein, and P. Strickland (1987). Direct action of 17β-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography.Cancer Res. 47:6052–6057.PubMedGoogle Scholar
  36. 36.
    S. A. Haslam and K. A. Nummy (1992). The ontogeny and cellular distribution of estrogen receptors in normal mouse mammary gland.J. Ster. Biochem. Mol. Biol. 42:589–595.Google Scholar
  37. 37.
    G. Zugmaier, C. Knabbe, C. Fritsch, S. Simpson, B. Ennis, M. E. Lippman, and R. B. Dickson (1991). Tissue culture conditions determine the effects of estrogen and growth factors on the anchorage independent growth of human breast cancer cell lines.J. Ster. Biochem. Mol. Biol. 39:681–685.Google Scholar
  38. 38.
    B. Van Der Burg, E. Kulkhoven, L. Isbruecken, and S. W. DeLaat (1992). Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions.J. Ster. Biochem. Mol. Biol. 42:457–465.Google Scholar
  39. 39.
    S. Neuenschwander, C. T. Roberts, and D. LeRoith (1995). Growth inhibition of MCF-7 breast cancer cells by stable expression of an insulin-like growth factor I receptor antisense ribonucleic acid.Endocrinology 136:4298–4303.PubMedGoogle Scholar
  40. 40.
    S. Z. Haslam (1991). Stromal-epithelial interactions in normal and neoplastic mammary gland. In M. Lippman and R. B. Dickson (eds.),Regulatory Mechanisms in Breast Cancer, Kluwer, Boston, pp. 401–420.Google Scholar
  41. 41.
    S. Z. Haslam, L. J. Counterman, and K. A. Nummy (1993). Effects of epidermal growth factor, estrogen, and progestin on DNA synthesis in mammary cellsin vivo are determined by the developmental state of the gland.J. Cell. Phys. 155:72–84.Google Scholar
  42. 42.
    E. Musgrove, C. L. Lee, R. L. Sutherland (1991). Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor α, epidermal growth factor receptor, c-fos, and c-myc genes.Mol. Cell Biol. 11:5032–5043.PubMedGoogle Scholar
  43. 43.
    S. C. Kiley, J. Welsh, C. J. Narvaez, and S. Jaken (1996). Protein kinaseC Isozymes and substrates in mammary carcinogenesis.J. Mam. Gland Biol. Neoplasia 1(2):177–187.Google Scholar
  44. 44.
    S. E. Bates, N. E. Davidson, E. M. Valverius, R. B. Dickson, C. E. Freter, J. P. Tam, and D. S. Salomon (1988). Expression of transforming growth factor alpha and its mRNA in human breast cancer: its regulation by estrogen and its possible functional significance.Mol. Endocrinol. 2:543–555.PubMedGoogle Scholar
  45. 45.
    S. C. Liu, B. Sanfilippo, I. Perroteau, R. Derynck, D. S. Salomon, and W. R. Kidwell (1987). Expression of transforming growth factor α (TGFα) in differentiated rat mammary tumors: estrogen induction of TGFα production.Mol. Endocrinol. 1:683–692.PubMedGoogle Scholar
  46. 46.
    R. B. King, D. Y. Wang, R. J. Daley, and P. D. Darbre (1989). Approaches to studying the role of growth factors in the progression of breast tumors from the steroid sensitive to insensitive state.J. Steroid Biochem. 34:133–138.PubMedGoogle Scholar
  47. 47.
    S. E. Bates, M. E. McManaway, M. E. Lippman, and R. B. Dickson (1986). Characterization of estrogen responsive transforming activity in human breast cancer cell lines.Cancer Res. 46:1707–1713.PubMedGoogle Scholar
  48. 48.
    S. R. Ahmed, B. Badger, C. Wright, and A. Manni (1991). Role of transforming growth factor-α (TGF-α) in basal and hormone-stimulated growth by estradiol, prolactin and progesterone in human and rat mammary tumor cells: studies using TGF-α and EGF receptor antibodies.J. Ster. Biochem. Mol. Biol. 38:687–693.Google Scholar
  49. 49.
    R. B. Dickson, K. K. Huff, E. M. Spencer, and M. E. Lippman (1986). Induction of epidermal growth factor-related polypeptides by 17-beta estradiol in MCF-7 human breast cancer cells.Endocrinology 118:138–142.PubMedGoogle Scholar
  50. 50.
    R. B. Dickson, M. McManaway, and M. E. Lippman (1986). Estrogen induced factors of breast cancer cells partially replace estrogen to promote tumor growth.Science 232:1540–1543.PubMedGoogle Scholar
  51. 51.
    R. B. Dickson, and M. E. Lippman (1988). Control of human breast cancer by estrogen, growth factors, and oncogenes. In M. E. Lippman, and R. B. Dickson (eds.),Breast Cancer: Cellular and Molecular Biology, Kluwer, Boston, pp. 119–165.Google Scholar
  52. 52.
    T. Saeki, A. Cristiano, M. J. Lynch, M. Brattain, N. Kim, N. Normanno, N. J. Kenney, and D. S. Salomon (1991). Regulation by estrogen through the 5′-flanking region of the transforming growth factor α gene.Mol. Endocrinol. 5:1955–1963.PubMedGoogle Scholar
  53. 53.
    I. Martinez-Lacaci, M. Saceda, G. Plowman, D. S. Salomon, and R. B. Dickson (1995). Regulation of amphiregulin gene expression by 12-O-tetradecanoylphorbol-13-acetate and 17-β-estradiol in human breast cancer cell lines.Endocrinology 136:3983–3992.PubMedGoogle Scholar
  54. 54.
    A. A. Colleta, L. M. Wakefield, F. V. Howell, D. Danielpour, M. Baum, and M. B. Sporn (1991). The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.J. Clin. Invest. 87:277–283.PubMedGoogle Scholar
  55. 55.
    L. C. Murphy and H. Dotzlau (1989). Regulation of transforming growth factor β messenger ribonucleic acid abundance in T47D human breast cancer cells.Mol. Endocrinol. 3:611–617.PubMedGoogle Scholar
  56. 56.
    B. A. Arrick, M. Korc, and R. Derynck (1990). Differential regulation of expression of three transforming growth factor-β species in human breast cancer cell lines by estradiol.Cancer Res. 50:299–303.PubMedGoogle Scholar
  57. 57.
    M. E. Herman and B. S. Katzenellenbogen (1994). Alterations in transforming growth factor α and β in production and cell responsiveness during the progression of MCF-7 human breast cancer cells to estrogen-autonomous growth.Cancer Res. 54:5867–5874.PubMedGoogle Scholar
  58. 58.
    A. Kopp, W. Jonet, M. Schahl, and C. Knabbe (1995). Transforming growth factor β2 (TGFβ2) levels in plasma of patients with metastatic breast cancer treated with tamoxifen.Cancer Res. 55:4512–4515.PubMedGoogle Scholar
  59. 59.
    M. Tzuckerman, X. Zhang, and M. Pfahl (1992). Inhibition of etrogen receptor activity by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate: a molecular analysis.Mol. Endocrinol. 5:1983–1992.Google Scholar
  60. 60.
    M. Saceda, C. Knabbe, R. B. Dickson, M. E. Lippman, D. Bronzart, R. L. Lindsay, M. Gottardis, and M. B. Martin (1991). Posttranscriptional destabilization of estrogen receptor mRNA in MCF-7 cells by 12-o-tetradecanoylphorbol-13-acetate.J. Biol. Chem. 266:17809–17814.PubMedGoogle Scholar
  61. 61.
    P. B. Joel, A. M. Traish, and D. Lamigan (1995). Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor.Endocrinology 9:1041–1052.Google Scholar
  62. 62.
    S. M. Aronica and B. S. Katzanellenbogen (1993). Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cAMP, and IGF-I.Mol. Endocrinol. 7:743–752.PubMedGoogle Scholar
  63. 63.
    R. J. Pietras, J. Arboleda, D. M. Reese, N. Wonguipat, M. D. Pegram, L. Romas, C. M. Gorman, M. G. Parker, M. X. Sliwkowski, and D. J. Slamon (1995).HER2 tyrosine kinase pathway target estrogen receptor and promotes hormone-independent growth in human breast cancer cells.Oncogene 10:2435–2446.PubMedGoogle Scholar
  64. 64.
    N. J. Kenney, T. Saeki, M. Gottardis, P. Garcia-Morales, M. P. Martin, H. Rochefort, N. Normanno, N. Kim, F. Ciardiello, and D. S. Salomon (1993). Expression of transforming growth factor α (TGFα) antisense mRNA inhibits estrogen-induced production of TGFα and estrogen-induced production of TGFα and estrogen-induced growth of estrogen-responsive human breast cancer cells.J. Cell. Physiol. 156:497–514.PubMedGoogle Scholar
  65. 65.
    K. B. Reddy, D. Yee, S. G. Hilsenbeck, R. J. Coffey, and C. K. Osborne (1994). Inhibition of estrogen-induced breast cancer cell proliferation by reduction in autocrine transforming growth factor α expression.Cell Growth Diff. 5:1215–1282.PubMedGoogle Scholar
  66. 66.
    I. Kim, A. Manni, J. Lynch, and J. M. Hammond (1991). Identification and regulation of insulin-like growth factor binding proteins produced by hormone-dependent and independent human breast cancer cell lines.Mol. Cell. Endocrinol. 78:71–78.PubMedGoogle Scholar
  67. 67.
    A. J. Stewart, M. D. Johnson, F. E. May, and B. R. Westley (1990). Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells.J. Biol. Chem. 265:21172–21178.PubMedGoogle Scholar
  68. 68.
    K. J. Cullen, M. E. Lippman, D. Chow, S. Hill, N. Rosen, and J. A. Zwiebel (1992). Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression.Mol. Endocrinol. 6:91–100.PubMedGoogle Scholar
  69. 69.
    Clarke, N. Brunner, D. Katz, P. Glanz, R. B. Dickson, M. E. Lippman, and F. G. Kern (1989). The effects of a constitutive production of TGFα on the growth of MCF-7 human breast cancer cellsin vitro andin vivo.Mol. Endocrinol. 3:372–380.PubMedGoogle Scholar
  70. 70.
    S. W. McLeskey, J. Kurebayaski, S. F. Honig, J. Zweibel, M. E. Lippman, R. B. Dickson, and F. G. Kern (1993). Fibroblast growth factor-4 transfection of MCF-7 cells produce cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifen-treated athymic nude mice.Cancer Res. 53:2168–2177.PubMedGoogle Scholar
  71. 71.
    L. C. Murphy, L. J. Murphy, D. Dubik, G. I. Bell, and R. Shiu (1988). Epidermal growth factor gene expression in human breast cancer cells: regulation of expression by progestins.Cancer Res. 48:4555–4560.PubMedGoogle Scholar
  72. 72.
    M. T. Travers, P. Barrett, U. Berger, Y. A. Luqmani, J. Gazet, T. J. Powles, and R. C. Coombes (1988). Growth factor expression in normal, benign, and malignant breast tissue.Br. Med. J. 296:1621–1630.Google Scholar
  73. 73.
    K. Stromberg, R. Hudgins, and D. N. Orth (1987). Urinary TGFs in neoplasia: immunoreactive TGFα in the urine of patients with disseminated breast carcinoma.Biochem. Biophys. Res. Commun. 144:1059–1067.PubMedGoogle Scholar
  74. 74.
    C. L. Artega, A. R. Hanauske, C. M Clark, C. K. Osborne, P. Hazarika, and R. L. Pardue (1988). Immunoreactive alpha transforming growth factor (IrαTGF) activity in effusions from cancer patients: a marker of tumor burden and patient prognosis.Cancer Res. 48:5023–5028.PubMedGoogle Scholar
  75. 75.
    M. Sairenji, K. Suzuki, K. Murakami, H. Motohashi, T. Okamoto, and M. Umeda (1997). Transforming growth factor activity in pleural and peritoneal effusions from cancer and non-cancer patients.Jpn. J. Cancer Res. (Gann) 78:814–817.Google Scholar
  76. 76.
    C. Qi, D. S. Liscia, G. Merlo, N. Normanno, G. Johnson, W. J. Gullick, F. Ciardiello, R. Brandt, N. Kim, N. Kenney, and D. S. Salomon (1994). Expression of transforming growth factor a, amphiregulin and cripto-1 in human breast carcinomas.Brit. J. Cancer 69:903–910.PubMedGoogle Scholar
  77. 77.
    S. LeJeune, R. Leck, E. Horak, G. Plowman, M. Greenall, and A. Harris (1993). Amphiregulin, epidermal growth factor receptor, and estrogen receptor expression in human primary breast cancer.Cancer Res. 53:3597–3602.PubMedGoogle Scholar
  78. 78.
    F. J. Lofts and W. J. Gullick (1992).c-erbB2 amplification and overexpression in human tumors. In R. B. Dickson and M. E. Lippman (eds.),Genes, Oncogenes and Hormones: Advances in Cellular and Molecular Biology of Breast Cancer, Kluwer, Norwell, pp. 161–179.Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Nicholas J. Kenney
    • 1
  • Robert B. Dickson
    • 1
  1. 1.Lombardi Cancer CenterGeorgetown UniversityWashington, D.C.

Personalised recommendations