Breast Cancer Research and Treatment

, Volume 47, Issue 3, pp 201–208 | Cite as

Role of IGF-I in normal mammary development

  • David L. Kleinberg


Growth hormone (GH) is now believed to be the pituitary factor that is responsible for mammary ductal morphogenesis. Mammary development at puberty occurs because of synergy between GH and estrogen on formation of terminal end buds (TEBs). TEBs extend into the substance of the mammary gland fat pad, resulting in ductal morphogenesis. Ultimately, the whole mammary fat pad accommodates a complex network of ducts. IGF-I or des(1-3) IGF-I mimic the actions of GH on TEB formation in hypophysectomized, gonadectomized rats. Since GH stimulates IGF-I mRNA within the mammary gland synergistically, we hypothesize that IGF-I partially mediates actions of GH in mammary gland development.

Studies in transgenic mice overexpressing IGF-I, des(1-3) IGF-I, or IGFBP-3 show that IGF-I causes ductal hypertrophy in the lactating mouse and prevention of post-lactational mammary gland involution. One of the mechanisms for this effect involves apoptosis.

The potential role of GH or IGF-I in mammary carcinogenesis, and the applicability of animal studies to humans, are discussed.

growth hormone IGF-I mammary gland development carcinogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nilsson A, Isgaard J, Lindahl A, Dahlstrom A, Skottner A, Isaksson OJP: Regulation by growth hormone of number of chondrocytes containing IGF-1 in rat growth plate. Science 233:571–574, 1986Google Scholar
  2. 2.
    Schlechter NL, Russell SM, Spencer EM, Nicoll CS: Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. Proc Natl Acad Sci USA 83:7932–7934, 1986Google Scholar
  3. 3.
    Ruan W, Newman CB, Kleinberg DL: Intact and aminoterminally shortened forms of insulin-like growth factor 1 induce mammary gland differentiation and development. Proc Natl Acad Sci USA 89:10872–10876, 1992Google Scholar
  4. 4.
    Ruan W, Catanese V, Wieczorek R, Feldman M, Kleinberg DL: 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. Endocrinol 136:1296–1302, 1995Google Scholar
  5. 5.
    Kleinberg DL, Ruan WF, Catanese V, Newman CB, Feldman M: Non-lactogenic effects of growth hormone on growth and insulin-like growth factor-I messenger ribonucleic acid of rat mammary gland. Endocrinol 126:3274–3276, 1990Google Scholar
  6. 6.
    Daniel CW, Silberstein GB: Postnatal development of the rodent mammary gland. In: Neville MC, Daniel CW (eds) The Mammary Gland: Development, Regulation, and Function. Plenum Press, New York, 1987, pp 1–36Google Scholar
  7. 7.
    Russo J, Russo IH: Susceptibility of the mammary gland to carcinogenesis. Am J Pathol 100:497–511, 1980Google Scholar
  8. 8.
    Russo J, Russo IH. DNA-labelling index and structure of the mammary gland as determinants of its susceptibility to carcinogenesis. J Natl Cancer Inst 61:1451–1459, 1978Google Scholar
  9. 9.
    Reece RP, Turner CW, Hill RT: Mammary gland development in the hypophysectomized albino rat. Proc Soc Exp Biol Med 34:204–217, 1936Google Scholar
  10. 10.
    Gardner WU: Growth of the mammary gland in hypophysectomized mice. Proc Soc Exp Biol Med 45:835–837, 1940Google Scholar
  11. 11.
    Lewis AA, Gomez ET, Turner CW: Mammary gland development with mammogen I in the castrated and the hypophysectomized rat. Endocrinol 30:37–47, 1942Google Scholar
  12. 12.
    Lyons WR, Johnson RE, Cole RD, Li CH: Mammary growth and lactation in male rats. In: Smith RW, Gaebler OH, Long CNH (eds) The Hypophyseal Growth Hormone, Nature and Actions. McGraw Hill, New York, 1955, pp 461–472Google Scholar
  13. 13.
    Lyons WR, Li CH, Johnson RE: The hormonal control of mammary growth and lactation. Rec Prog Horm Res 14:219–248, 1958Google Scholar
  14. 14.
    Lyons WR: Hormonal synergism in mammary growth. Proc Royal Soc (London) 149:303–325, 1993Google Scholar
  15. 15.
    Feldman M, Ruan W, Cunningham BC, Wells JA, Kleinberg DL: Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland. Endocrinol 133:1602–1608, 1993Google Scholar
  16. 16.
    Glimm DR, Baracos VE, Kennelly JJ: Molecular evidence for the presence of growth hormone receptors in the bovine mammary gland. J Endocrinol 126:R5–R8, 1990Google Scholar
  17. 17.
    Hauser SD, McGrath MF, Collier RJ, Krivi GG: Cloning and in vivo expression of bovine growth hormone receptor mRNA. Mol Cell Endocrinol 72:187–200, 1990Google Scholar
  18. 18.
    Jammes H, Gaye P, Belair L, Djiane J: Identification and characterization of growth hormone receptor mRNA in the mammary gland. Mol Cell Endocrinol 75:27–35, 1991Google Scholar
  19. 19.
    Lincoln DT, Waters MJ, Breipohl W, Sinowatz F, Lobie PE: Growth hormone receptors expression in the proliferating rat mammary gland. Acta Histochemica Suppl Vol 40:S47–S49, 1990Google Scholar
  20. 20.
    Feldman M, Ruan W, Kleinberg DL: Measurement of growth hormone receptor in rat mammary gland [abstract]. 75th Annual Meeting of the Endocrine Society, 469A, 1993Google Scholar
  21. 21.
    Murphy LJ, Bell GI, Friesen HG: Tissue distribution of insulin-like growth factor I and II messenger ribonucleic acid in the adult rat. Endocrinol 120:1279–1282, 1987Google Scholar
  22. 22.
    Walden PD, Ruan W, Feldman M, Kleinberg DL: Evidence that the mammary fat pad mediates the action of growth hormone in mammary gland development. Endocrinology 139 (in press), 1998Google Scholar
  23. 23.
    Coleman S, Silberstein GB, Daniel CW: Ductal morphogenesis in the mouse mammary gland: Evidence supporting a role for epidermal growth factor. Develop Biol 127:304–315, 1988Google Scholar
  24. 24.
    Vonderhaar BK, Ziska SE: Hormonal regulation of milk protein gene expression. Annu Rev Physiol 51:641–652, 1989Google Scholar
  25. 25.
    Jahn GA, Edery M, Belair L, Kelly PA, Djiane J: Prolactin receptor gene expression in rat mammary gland and liver during pregnancy and lactation. Endocrinol 128:2976–2984, 1991Google Scholar
  26. 26.
    Rosen JM, Woo SLC, Comstock JP: Regulation of casein messenger RNA during the development of the rat mammary gland. Biochem 14:2895–2903, 1975Google Scholar
  27. 27.
    Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM: 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. Endocrinol 136 (in press)Google Scholar
  28. 28.
    Neuenschwander S, Schwartz A, Wood TL, Roberts CTJ, Henninghausen L, LeRoith D: Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J Clin Invest 97:2225–2232, 1996Google Scholar
  29. 29.
    Kleinberg DL, Niemann W, Flamm E, Cooper P, Babitsky G, Valensi Q: Primate mammary development: Effects of hypophysectomy, prolactin inhibition and growth hormone administration. J Clin Invest 75:1943–1950, 1985Google Scholar
  30. 30.
    Newman CB, Cosby H, Worsley IG, Monaco ME, Kleinberg DL: Evidence that the human pituitary contains non-hPRL, non-hGH mammary mitogens [abstract]. 68th Annual Meeting of the Endocrine Society, Abstract 15, 1986Google Scholar
  31. 31.
    Newman CB, Cosby H, Friesen H, Stampfer MJ, Monaco ME, Kleinberg DL: Novel human pituitary factors stimulate growth of mammary cancer cells and normal mammary gland. Clin Res 34:645, 1986Google Scholar
  32. 32.
    Newman CB, Cosby H, Friesen HG, Feldman M, Cooper P, DeCrescito V, Pilon M, Kleinberg DL: Evidence for a non-prolactin, non-growth hormone mammary mitogen in the human pituitary gland. Proc Natl Acad Sci USA 84:8110–8114, 1987Google Scholar
  33. 33.
    Yee D, Paik S, Lebovie S, Marcus RR, Favoni RE, Cullen KJ, Lippman ME, Rosen N: Analysis of insulin-like growth factor 1 gene expression in malignancy: Evidence for a paracrine role in human breast cancer. Mol Endocrinol 3:509–517, 1989Google Scholar
  34. 34.
    Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FCJ, Allred DC, Osborne CK: Blockade of the type 1 somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84:1418–1423, 1989Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • David L. Kleinberg
    • 1
  1. 1.Veterans Administration and New York University Medical CentersNew YorkUSA

Personalised recommendations