IGF-I, GH, and Sex Steroid Effects in Normal Mammary Gland Development

Abstract

Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of GH to stimulate production of IGF-I in the mammary gland. Growth hormone binds to its receptor in the mammary fat pad, after which production of IGF-I mRNA and IGF-I protein occurs. It is likely that IGF-I then works through paracrine means to stimulate formation of TEBs, which then form ducts by bifurcating or trifurcating and extending through the mammary fat pad. By the time pubertal development is complete a tree-like structure of branching ducts fills the rodent mammary fat pad. In addition to requiring IGF-I in order to act, estradiol also directly synergizes with IGF-I to enhance formation of TEBs and ductal morphogenesis. Together they increase IRS-1 phosphorylation and cell proliferation, and inhibit apoptosis. In fact, the entire process of ductal morphogenesis, in oophorectomized IGF-I(-/-) knockout female mice, can occur as a result of the combined actions of estradiol and IGF-I. IGF-I also permits progesterone action in the mammary gland. Together they have been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-I and estradiol. Although both progesterone and estradiol synergize with IGF-I by increasing IGF-I action parameters, there must be other, as yet unknown mechanisms that account for the anatomical differences in the different forms of ductal morphogenesis observed (hyperplasia in response to IGF-I plus estradiol and single layered ducts in response to IGF-I plus progesterone).

Insulin-like growth factor-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women

“…Importantly, GH and IGF-1 signalling, together with estrogens, is essential for the development of the mammary gland, particularly the terminal end-buds. It has also been found that during lactation, IGF-1 plays an important role in the maintenance of the adult mammary gland [48][49][50]. Furthermore, percent mammographic density refers to the structure of the adipose, epithelial and connective tissue in the breast [51].…”

Growth hormone is a cellular senescence target in pituitary and nonpituitary cells

“…GH secreted by the pituitary gland acts as an endocrine regulator in multiple tissues (52)(53)(54)(55) and elicits peripheral IGF1 by signaling through the membrane-associated GHR linked to Jak2 (56)(57)(58)(59)(60). It was shown that GH is also expressed locally in nonpituitary cells (including colon, prostate, breast, and brain), where it feeds back to membrane-associated GHR to signal in an autocrine fashion via Jak2 (61,62).…”

Disruption of reelin signaling alters mammary gland morphogenesis

“…The retraction of TEBs in mutants, even in the absence of complete ductal elongation, suggested that maturation of the gland had occurred and that limited ductal arborization was a persistent and permanent phenotype. TEBs depend on signals from a variety of growth factors, including IGF-1, growth hormone and sex steroids (Kleinberg and Ruan, 2008), and these signals may also be disrupted in reeler and Dab1 mutants.…”