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

  title={IGF-I: An Essential Factor in Terminal End Bud Formation and Ductal Morphogenesis},
  author={David L. Kleinberg and Mark Feldman and Weifeng Ruan},
  journal={Journal of Mammary Gland Biology and Neoplasia},
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… 

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

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, which has been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-i and estradiol.

Growth hormone, acting in part through the insulin-like growth factor axis, rescues developmental, but not metabolic, activity in the mammary gland of mice expressing a single allele of the prolactin receptor.

It is suggested that GH can improve mammary development in PRLR(+/-) mice, but that it fails to enhance metabolic activity.

Local insulin-like growth factor-II mediates prolactin-induced mammary gland development.

Induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors.

The Insulin-Like Growth Factors (IGFs) and IGF Binding Proteins in Postnatal Development of Murine Mammary Glands

A role for the IGFs and IGFBPs are supported as local mediators of postnatal mammary gland growth and differentiation in mice mammary glands in organ culture.

Expression of the insulin-like growth factor binding proteins during postnatal development of the murine mammary gland.

Important functions for the family of IGFBPs during postnatal growth and differentiation of the mammary epithelium are suggested.

The IGF System in Mammary Development and Breast Cancer

  • D. YeeT. Wood
  • Biology, Medicine
    Journal of Mammary Gland Biology and Neoplasia
  • 2008
The IGFs, receptors and binding proteins have emerged as critical mediators in growth of mammary/breast epithelium both in normal developmental processes and in tumorigenesis and their role as endocrine versus autocrine/ paracrine growth factors is reviewed.

Insulin-like growth factor binding proteins and mammary gland development.

This review examines the evidence from in vitro studies and the attempts to examine in vivo actions utilising models with IGFBP deficiency or over-expression and believes that recent findings place some of the IGFBPs in a larger family of extracellular proteins, the secreted cysteine-rich protein (CCN) family, which have similar structural domains and are heavily implicated in tissue re-modeling and morphogenesis.

Developmental Changes in Insulin‐like Growth Factor I Receptor Gene Expression in the Mouse Mammary Gland

Results demonstrate that a developmental IGF‐IR gene expression pattern exists in the mouse mammary gland and that increases in gene expression at specific phases of development may reflect an important role for IGF‐I/IGF‐IR at those phases ofDevelopment.

IGF and Insulin Action in the Mammary Gland: Lessons from Transgenic and Knockout Models

Results obtained from the application of transgenic and knockout mice to determine the roles of insulin and insulin-like growth factors (IGF)3 in the regulation of mammary gland development, lactation and tumorigenesis are focused on.

Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis

A clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided.



Insulin-Like Growth Factor I Is Essential for Terminal End Bud Formation and Ductal Morphogenesis during Mammary Development1.

The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present.

Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model.

It is demonstrated that IGF-I and IGFBP-3 may modulate the involutionary process of the lactating mammary gland by influencing the remodeling of mammary tissue during involution.

Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland.

It is shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development, suggesting that GH receptors play a central role in this process.

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.

These studies indicate that IGF-I can have a small independent effect on mammary development, but like GH, E2 is required for a full effect, and that the action of E2 on Mammary development may take place at multiple sites.

The Insulin-Like Growth Factors (IGF) and IGF Type I Receptor during Postnatal Growth of the Murine Mammary Gland: Sites of Messenger Ribonucleic Acid Expression and Potential Functions* * This work was supported, in part, by NIH Grant DK-48103 (to T.L.W.).

In situ hybridization analyses determined that IGF-I, IGF-II, and IGF-IR messenger RNAs were expressed in the highly proliferative terminal end buds during pubertal ductal growth and correlated with the pattern of rapidly proliferating cells, suggesting a potential autocrine or paracrine role for IGF- II as a mitogen for ductal epithelial cells.

Early Mammary Development: Growth Hormone and IGF-1

  • D. Kleinberg
  • Biology
    Journal of Mammary Gland Biology and Neoplasia
  • 2004
This minireview focuses on the hormonal control of early mammary development with special emphasis on the roles of growth hormone and IGF-1.

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.

GHR and GHBP mRNAs and proteins are expressed in both the epithelium and the stroma of mammary glands of virgin, pregnant, and lactating mice and indicate that the actions of GH in the mammary gland are both direct through its binding tothe epithelia, and indirect by binding to theStroma and stimulation of IGF-I production which, in turn, affects mammary epithelial development.

Mammary gland development is mediated by both stromal and epithelial progesterone receptors.

This study suggests that the regulation of mammary gland development by steroid hormones is mediated by distinct effects of the stromal and epithelial PR and differential growth factor expression.