IGF-I: An Essential Factor in Terminal End Bud Formation and Ductal Morphogenesis

  • David L. Kleinberg
  • Mark Feldman
  • Weifeng Ruan


Growth hormone (GH)3 is essential for rodent mammary gland development during puberty.It binds to GH receptors in the stromal compartment of the mammary gland and stimulatesIGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locallyproduced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structuresthat lead the process of mammary gland development during puberty. Subsequent studieshave in large measure proven this hypothesis. They include the observations that mammarydevelopment was grossly impaired in female mice deficient in IGF-I (IGF-I(−/−) knockoutmice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammarydevelopment while treatment with GH + E2 did not. Thus, the full phenotypic action of GHin mammary gland development is mediated by IGF-I. We have demonstrated one effect ofGH on the mammary gland that does not appear to be mediated by the action of IGF-I. GHincreased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammaryfat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis duringpubertal mammary development, other data suggest that IGF-I might also be of importanceduring pregnancy and lactation. In summary, the earliest phase of pubertal mammarydevelopment (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormoneshave been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-inducedIGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for laterstages of mammary development, as well.

Growth hormone pubertal mammary development insulin-like growth factor I estrogen receptor IGF-I knockout animals 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    W. Ruan, C. B. Newman, and D. L. Kleinberg (1992). Intact and aminoterminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and developinsulin-ment. Proc. Natl. Acad. Sci. U.S.A. 89:10872–10876.Google Scholar
  2. 2.
    R. P. Reece, C. W. Turner, and R. T. Hill (1936). Mammary gland development in the hypophysectomized albino rat. Proc. Soc. Exp. Biol. Med. 34:204–217.Google Scholar
  3. 3.
    W. U. Gardner, and A. White (1941). Mammary growth in hypophysectomized male mice receiving estrogen prolactin. Proc. Soc. Exp. Biol. Med. 48:590–592.Google Scholar
  4. 4.
    A. A. Lewis, E. T. Gomez, and C.W. Turner (1942). Mammary gland development with mammogen I in the castrated and the hypophysectomized rat. Endocrinology 30:37–47.Google Scholar
  5. 5.
    W. R. Lyons, C. H. Li, and R. E. Johnson (1958). The hormonal control of mammary growth and lactation. Rec. Prog. Horm. Res. 14:219–248.Google Scholar
  6. 6.
    S. Nandi (1958). Endocrine control of mammary-gland develgenesis opment and function in the C3 11/HE Crgl mouse. J. Natl. Cancer Inst. 21(6):1039–1062.Google Scholar
  7. 7.
    W. R. Lyons (1993). Hormonal synergism in mammary growth. Proc Royal Soc. (London) 149:303–325.Google Scholar
  8. 8.
    W. R. Lyons, R. E. Johnson, R. D. Cole, and C. H. Li (1955). Mammary growth and lactation in male rats. In R. W. Smith, O. H. Gaebler, and C. N. H. Long, (eds.), The Hypophyseal Growth Hormone, Nature and Actions, New York, McGraw Hill, pp. 461–472.Google Scholar
  9. 9.
    D. L. Kleinberg, W. Niemann, E. Flamm, P. Cooper, G. Babit-sky, and Q. Valensi (1985). Primate mammary development: Effects of hypophysectomy, prolactin inhibition and growth hormone administration. J. Clin. Invest. 75:1943–1950.Google Scholar
  10. 10.
    D. L. Kleinberg, W. F. Ruan, V. Catanese, C. B. Newman, and M. Feldman (1990). Nonlactogenic effects of growth hormone on growth and insulin-like growth factor-I messenger ribonucleic acid of rat mammary gland. Endocrinology 126: 3274–3276.Google Scholar
  11. 11.
    D. L. Kleinberg (1997). Early mammary development: Growth hormone and IGF-1. J. Mam. Gland Biol. Neoplasia 2:49–57.Google Scholar
  12. 12.
    M. Feldman, W. Ruan, B. C. Cunningham, J. A. Wells, and D. L. Kleinberg (1993). Evidence that the growth hormone receptor mediates differentiation and development of the mamevidence mary gland. Endocrinology 133:1602–1608.Google Scholar
  13. 13.
    Y. N. Ilkbahar, G. Thordarson, I. G. Camarillo, and F. Tala-mantes (1999). Differential expression of the growth hormone receptor and growth hormone-binding protein in epithelia and stroma of the mouse mammary gland at various physiological stages. J. Endocrinol. 161:77–87.Google Scholar
  14. 14.
    C. W. Daniel and G. B. Silberstein (1987). Postnatal develop-ment of the rodent mammary gland. In M. C. Neville and C.W. Daniel, (eds.), The Mammary Gland: Development, Regulation, and Function, New York, Plenum Press, pp. 1–36.Google Scholar
  15. 15.
    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
  16. 16.
    C. B. Newman, H. Cosby, H. G. Friesen, M. Feldman, P. Cooper, V. DeCrescito, M. Pilon, and D. L. Kleinberg (1987). Evidence for a nonprolactin, nongrowth hormone mammary mitogen in the human pituitary gland. Proc. Natl. Acad. Sci. U.S.A. 84:8110–8114.Google Scholar
  17. 17.
    W. Ruan, V. Catanese, R. Wieczorek, M. Feldman, and D. L. Kleinberg (1995). Estradiol enhances the stimulatory effect of insulin-like growth factor-I (IGF-I) on mammary development and growth hormone-induced IGF-I messenger ribonucleic acid. Endocrinology 136:1296–1302.Google Scholar
  18. 18.
    M. M. Richert and T. L. Wood (1999). The Insulin-like growth factors (IGF) and the IGF Type I receptor during postnatal growth of the murine mammary gland: Sites of messenger ribonucleic acid expression and potential functions. Endocri-nology 140:454–461.Google Scholar
  19. 19.
    D. L. Kleinberg and W. Ruan (1999). The crucial roles of developinsulin-like growth factor I and growth hormone in mammary gland development. In D. LeRoith (ed), Advances in Molecular and Cellular Endocrinology, Stamford, JAI Press Inc. pp. 225–238.Google Scholar
  20. 20.
    R. C. Hovey, H. W. Davey, D. D. S. Mackenzie, and T. B. McFadden (1998). Ontogeney and epithelial-stromal interac-tions regulate IGF expression in the ovine mammary gland. Mol. Cell Endocrinol. 136:139–144.Google Scholar
  21. 21.
    P. D. Walden, W. F. Ruan, M. Feldman, and D. L. Kleinberg (1998). Evidence that the mammary gland fat pad mediates the action of growth hormone in mammary gland development. Endocrinology 139:659–662.Google Scholar
  22. 22.
    W. Ruan and D. L. Kleinberg (1999). Insulin-like growth factor-I is essential for terminal end bud formation and ductal morpho-develgenesis during mammary development. Endocrinology 140: 5075–5081, 1999.Google Scholar
  23. 23.
    R. C. Humphreys, J. Lydon, B. W. O'Malley, and J. M. Rosen (1997). Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol. Endocri-nol. 11:801–811.Google Scholar
  24. 24.
    R. C. Humphreys, J. P. Lydon, B.W. O'Malley, and J. M. Rosen (1997). Use of PRKO mice to study the role of progesterone in mammary gland development. J. Mam. Gland Biol. Neopla-sia 2:343–354.Google Scholar
  25. 25.
    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.Google Scholar
  26. 26.
    S. Z. Haslam and G. Shyamala (1981). Relative distribution of estrogen and progesterone receptors among epithelial, adipose, and connective tissue components of the normal mammary gland. Endocrinology 108:825–830.Google Scholar
  27. 27.
    S. Z. Haslam and K. A. Nummy (1992). The ontogeny and cellular disltribution of estrogen receptors in normal mouse mammary gland. J. Steroid Biochem. Molec. Biol. 42:589–595.Google Scholar
  28. 28.
    G. B. Silberstein, K. Van Horn, G. Shyamala, and C.W. Daniel (1994). Essential role of endogenous estrogen in directly stimu-lating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 134:84–90.Google Scholar
  29. 29.
    M. Feldman, W. Ruan, I. Tappin, R. Wieczorek, and D. L. Kleinberg (1999). The effect of GH on estrogen receptor expression in the rat mammary gland. J. Endocrinol. 163:515–522, 1999.Google Scholar
  30. 30.
    D. L. Hadsell, N. M. Greenberg, J. M. Fligger, C. R. Baumrucker, and J. M. Rosen (1996). Targeted expression of des(1–3) human insulin-like growth factor I (IGF-I) in transgenic mice influences mammary gland development and IGF-binding protein expression. Endocrinology 136:321–330.Google Scholar
  31. 31.
    S. Neuenschwander, A. Schwartz, T. L. Wood, C. T. J. Roberts, L. Henninghausen, and D. LeRoith (1996). Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J. Clin. Invest. 97:2225–2232.Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • David L. Kleinberg
    • 1
    • 2
  • Mark Feldman
    • 1
  • Weifeng Ruan
    • 1
  1. 1.Departments of MedicineNew York University School of Medicine and Department of Veterans Affairs Medical CenterNew York
  2. 2.DVA Medical CenterNew York

Personalised recommendations