IGF-I: An essential factor in terminal end bud formation and ductal morphogenesis

Growth hormone (GH)(3) is essential for rodent mammary gland development du ring puberty. It binds to GH receptors in the stromal compartment of the ma mmary gland and stimulates IGF-I mRNA expression. These findings lead to th e hypothesis that GH acts through locally produced IGF-I, which in turn, ca uses development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies hav e in large measure proven this hypothesis. They include the observations th at mammary development was grossly impaired in female mice deficient in IGF -I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E-2) restored pubertal mammary development while treatment with GH + E-2 did not. Thus, the full phenotypic action of GH in mammary gland d evelopment is mediated by IGF-I. We have demonstrated one effect of GH on t he mammary gland that does not appear to be mediated by the action of IGF-I . GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the crit ical role of the GW/IGF-I axis during pubertal mammary development, other d ata suggest that IGF-I might also be of importance during pregnancy and lac tation. In summary, the earliest phase of pubertal mammary development (for mation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or TGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis , and may, in fact, be necessary for later stages of mammary development, a s well.