In 1957 Salmon and Daughaday could never have imagined that the sulfation factor they discovered [1] - later named insulin-like growth factor I or IGF-I - would turn out to have so many important biological functions [2]. We now know that IGF-I possesses a plethora of biologic actions on cell growth and death, linear growth, embryonic and postnatal growth, ovarian function, and protein and carbohydrate metabolism [2]. Several recent articles focus our attention on another important action of IGF-I: modulation of mammary gland function.
A number of lines of experimental evidence to suggest that IGF-I mediates the important actions of growth hormone (GH) in normal mammary development at the time of puberty. Several years ago, we demonstrated that hGH increased mammary gland IGF-I mRNA content, as assessed by solution hybridization/RNase protection assay [3]. More recently we also showed that administration of estradiol enhanced the stimulatory effects of hGH on mammary gland IGF-I mRNA [4]. Additionally, locally implanted IGF-I and des(1-3)IGF-I significantly increased the number of terminal end buds (TEBs) in mammary glands of hypophysectomized, castrated sexually immature male rats also treated with estradiol [5], and in females rats similarly treated [4]. These anatomical changes mimicked those of pubertal development.
Based on the results of hormone replacement studies to identify individual pituitary hormones responsible for mediating the pituitary gland's pivotal role in mammary development [6], Lyons and colleagues were the first investigators to suggest that GH was central to the process of mammary gland development [7]. Our more recent studies have repopularized and extended the findings of Lyons. We noted that both lactogenic and non-lactogenic GHs were far more potent than prolactins (PRLs) from the same species in the process of mammary development [3]. Furthermore, we found that the GH receptor mediated mammary gland differentiation and development induced by pituitary hormones. In these studies, native and mutant forms of GH, PRL and placental lactogen were tested for their effects on mammary development (together with estradiol, E2), binding to GH receptor, and ability to activate PRL receptor [8]. Only natural or mutant hormones with high binding affinity to GH receptors were found to induce mammary development, regardless of their lactogenicity. Therefore, we concluded that GH was the pituitary hormone most central to mammary development, and that it probably acts, at least in part, through local production of IGF-I in stroma [9]. It should be noted that in transgenic mice expressing hGH (which binds to both PRL- and GH-receptors), the animals developed precocious mammary gland development and milk protein synthesis [10]. The role of PRL in mammary development has not been included here, although PRL did not increase IGF-I mRNA [3] in rat mammary gland. Nevertheless, PRL may still play a role in the early development of the mammary gland in addition to its well documented effect in lactogenesis [11]. GH may also have direct effects on specific steps in mammary development that may not be mediated by IGF-I, although these have not been carefully delineated.
Despite the fact that both GH and IGF-I can stimulate a small amount of new TEB formation in the absence of E2, and that E2 in the absence of the pituitary has no effect on induction of these structures, E2 is extremely important in pubertal development of the mammary gland [12]. Studies showing that pure antiestrogens implanted in the substance of mouse mammary glands locally inhibit ductal mammogenesis suggest that estrogens act directly on the mammary gland, rather than through intermediaries produced at distant sites, such as the pituitary gland [13]. This does not rule out the possibility that E2 acts locally in the mammary gland through production of intermediaries such as TGFa, which also causes mammary hyperplasia when it is overexpressed in transgenic mice [14,15]. Assuming that mammary development occurs via the cascade of peptide hormones referred to above, the site of E2 interaction with peptide hormones probably occurs after IGF-I production, since E2 is known to synergize with IGF-I in the absence of GH [4].
Des(1-3)IGF-I is more potent than native IGF-I in stimulating mammary gland development, because this aminoterminally shortened form of IGF-I has a lower affinity for insulin-like growth factor binding proteins (IGFBPs) [16]. The effects of IGFBPs on mammary gland function are likely to be very important. Both IGF-I and des(1-3)IGF-I are known to stimulate IGFBP production in bovine mammary epithelial cells [17]. IGF-I also stimulates at least one IGFBP in milk from lactating mice [18]. IGFBP-1 has been found to inhibit E2-induced MCF-7 cell growth [19], and IGFBP-3, which can inhibit IGF-I action by binding to it, has also been found to bind to the cell surface of mammary tumor cells and inhibit their growth [20]. Whether IGF-I in the mammary gland needs to be converted to des(1-3) IGF-I by a protease, in order to act without interference by IGFBP, has not been ascertained [21].
Two recent articles suggest that overexpression of IGF-I alters mammary glandular structures in fully developed adult animals at the time of lactation. Hadsell and colleagues, using an elegant experimental model of transgenic mice, studied the effects of IGF-I or des(1-3) IGF-I, an aminoterminally shortened form of IGF-I, on the mammary gland during and after lactation [18] (
information on transgenic mice). The transgene was coupled to the whey acidic protein gene promoter to allow for mammary specific expression. In this model, IGF-I production in the mammary gland is partially under the control of the hormones of pregnancy and lactation, which cause expression of the rat whey acidic protein gene and therefore, the IGF-I gene coupled to it. In these transgenic animals, IGF-I appeared to prevent mammary gland involution after lactation and caused ductile hypertrophy. In a similar animal model, in which IGF-I or BP-3 were overexpressed (information on transgenic mice), Neuenschwander and colleagues found that both proteins inhibited apoptosis of mammary glandular cells [22]. Although the relevance of the findings in these two studies to normal physiology is unclear, this model provides investigators with a tool to study the effects of localized, chronic IGF-I stimulation on mammary morphology (in primiparous or multiparous animals), lactation, and possibly carcinogenesis.The mechanism by which des(1-3) IGF-I induces new mammary gland development [4,5], or inhibits post-lactational involution [18], is not fully known. Although inhibition of apoptosis is likely one of the mechanisms involved [2,22], a positive effect on cell proliferation and differentiation may also be important. In the case of mammary development in sexually immature animals, an effect of IGF-I on new glandular proliferation must be important since TEBs are not previously present. Inhibition of apoptosis might also play a role in pubertal development. Thus, the importance of IGF-I in mammary development and function at different phases of life, its dependence of GH, and the mechanisms by which it acts, will likely require years of further investigation. Implied in the process of understanding the effects of IGF-I on mammary gland development at various stages of life is the eventual possibility that those observations might be applicable to better understanding and treating breast cancer.
*Excerpted from and based on a previously published editorial in Endocrinology (137:1-2, 1996).
References
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2. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Rev 1995;16(1):3-34.
3. 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 1990;126:3274-6.
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 1995;136:1296-302.
5. Ruan W, Newman CB, Kleinberg DL. Intact and aminoterminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development. Proc Natl Acad Sci USA 1992;89:10872-6.
6. Reece RP, Turner CW, Hill RT. Mammary gland development in the hypophysectomized albino rat. Proc Soc Exp Biol Med 1936;34:204-17.
7. Lyons WR, Johnson RE, Cole RD, et al.; Smith RW, Gaebler OH, Long CNH, editors. The Hypophyseal Growth Hormone, Nature and Actions. New York: McGraw Hill, 1955;Mammary growth and lactation in male rats. p. 461-72.
8. 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 1993;133:1602-8.
9. Yee D, Paik S, Lebovic 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 1989;3:509-17.
10. Bchini O, Andres AC, Schubaur B, Mehtali M, LeMeur M, Lathe R, Gerlinger P. Precocious mammary gland development and milk protein synthesis in transgenic mice ubiquitously expressing human growth hormone. Endocrinol 1991;128:539-46.
11. Plaut K, Ikeda M, Vonderhaar BK. Role of growth hormone and insulin-like growth factor-I in mammary development. Endocrinol 1993;133:1843-8.
12. Gardner WU, White A. Mammary growth in hypophysectomized male mice receiving estrogen prolactin. Proc Soc Exp Biol Med 1941;48:590-2.
13. Silberstein GB, Van Horn K, Shyamala G, Daniel CW. Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinol 1994;134:84-90.
14. Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGF_ in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast. Cell 1990;61:1121-35.
15. Matsui Y, Halter SA, Holt JT, Hogan BLM, Coffey RJ. Development of mammary hyperplasia and neoplasia in MMTV-TGF_ transgenic mice. Cell 1990;61:1147-55.
16. Carlsson-Skwirut C, Lake M, Hartmanis M, Hall K, Ara VR. A comparison of the biological activity of the recombinant intact and truncated insulin-like growth factor 1 (IGF-1). Biochim Biophys Acta 1989;1011:192-7.
17. McGrath MF, Collier RJ, Clemmons DR, Busby WH, Sweeney CA, Krivi GG. The direct in vitro effect of insulin-like growth factors (IGFs) on normal bovine mammary cell proliferation and production of IGF binding proteins. Endocrinol 1991;129:671-8.
18. 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. Endocrinolgy 1997;137:321-30.
19. Figueroa JA, Sharma J, Jackson JG, McDermott MJ, Hilsenbeck SG, Yee D. Recombinant insulin-like growth factor binding protein-1 inhibits IGF-I, serum, and estrogen-dependent growth of MCF-7 human breast cancer cells. J Cell Physiol 1993;157:229-36.
20. Oh Y, Muller HL, Lamson G, Rosenfeld RG. Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells: cell surface binding and growth inhibition. J Biol Chem 1993;268:14964-71.
21. Yamamoto H, Murphy LJ. N-Terminal truncated insulin-like growth factor-I in human urine. J Clin Endocrinol Metab 1995;80:1179-83.
22. 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 1996;97:2225-32.
contributed by
David L. Kleinberg
New York University Medical Center
and VA Medical Center
New York, New York 10016
tel. (212)
FAX (212)
(e-mail: monacom@is2.nyu.edu)
contributed: June, 1996 |
