Free IGF-I Promotes Accelerated Mammary Gland Development.

We have used quantitative RT-PCR to analyse the mRNA expression profile of the major components of the IGF axis in different stages of murine mammary gland development, including late pregnancy, lactation and involution. We have shown that all the genes studied, IGF-I, IGF-II, IGF receptor (IGFR) and IGF-binding protein (IGFBP)-1 to -6, were expressed in every stage, albeit at greatly differing levels and displaying unique expression profiles between developmental stages. IGF-I was always expressed at significantly higher levels than either IGF-II or IGFR. This suggests that IGF-I may be the more important IGF during mammary morphogenesis. Overall, IGFBP-3 demonstrated the highest level of expression of any of the IGFBP genes throughout all the developmental stages studied. However, within developmental stages, by far the highest level of expression of any of the IGFBPs was that of IGFBP-5 at day 2 of involution; this was almost an order of magnitude higher than any of the other IGFBP levels recorded. This corroborated our previous findings that the levels of IGFBP-5 protein are highly elevated in the involuting mammary gland, and demonstrated that this up-regulation of IGFBP-5 operates at the level of transcriptional control or message stability. Comparison of the expression profile for these different genes would strongly suggest that they are likely to have differential functions throughout mammary gland development, and also highlights potential interactions and co-regulation between different members of this axis. In addition, our results have identified some similarities and differences in the expression of IGFBPs between the mouse mammary epithelial cell line, HC11, and the normal mammary gland which are worthy of study, most notably the differential regulation of IGFBP-2 and the site of expression of IGFBP-4 and -6. Overall, this study has demonstrated the importance and complexity of the IGF axis during mammary gland development and provides a valuable resource for future research in this area.

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

Journal of Mammary Gland Biology and Neoplasia ◽

10.1007/s10911-008-9103-7 ◽

2008 ◽

Vol 13 (4) ◽

pp. 353-360 ◽

Cited By ~ 45

Author(s):

David L. Kleinberg ◽

Weifeng Ruan

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Sex Steroid ◽

Normal Mammary Gland ◽

Igf I ◽

Gland Development

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Elevated Circulating IGF-I Promotes Mammary Gland Development and Proliferation

Endocrinology ◽

10.1210/en.2010-0792 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5751-5761 ◽

Cited By ~ 20

Author(s):

Dara Cannata ◽

Danielle Lann ◽

Yingjie Wu ◽

Sebastien Elis ◽

Hui Sun ◽

...

Keyword(s):

Mammary Gland ◽

Animal Studies ◽

Mammary Gland Development ◽

Mammary Development ◽

Mammary Epithelial ◽

Epithelial Development ◽

Igf I ◽

Luminal Cells ◽

Gland Development ◽

Major Mediator

Animal studies have shown that IGF-I is essential for mammary gland development. Previous studies have suggested that local IGF-I rather than circulating IGF-I is the major mediator of mammary gland development. In the present study we used the hepatic IGF-I transgenic (HIT) and IGF-I knockout/HIT (KO-HIT) mouse models to examine the effects of enhanced circulating IGF-I on mammary development in the presence and absence of local IGF-I. HIT mice express the rat IGF-I transgene under the transthyretin promoter in the liver and have elevated circulating IGF-I and normal tissue IGF-I levels. The KO-HIT mice have no tissue IGF-I and increased circulating IGF-I. Analysis of mammary gland development reveals a greater degree of complexity in HIT mice as compared to control and KO-HIT mice, which demonstrate similar degrees of mammary gland complexity. Immunohistochemical evaluation of glands of HIT mice also suggests an enhanced degree of proliferation of the mammary gland, whereas KO-HIT mice exhibit mammary gland proliferation similar to control mice. In addition, HIT mice have a higher percentage of proliferating myoepithelial and luminal cells than control mice, whereas KO-HIT mice have an equivalent percentage of proliferating myoepithelial and luminal cells as control mice. Thus, our findings show that elevated circulating IGF-I levels are sufficient to promote normal pubertal mammary epithelial development. However, HIT mice demonstrate more pronounced mammary gland development when compared to control and KO-HIT mice. This suggests that both local and endocrine IGF-I play roles in mammary gland development and that elevated circulating IGF-I accelerates mammary epithelial proliferation.

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Delayed Mammary Gland Involution in Mice with Mutation of the Insulin-Like Growth Factor Binding Protein 5 Gene

Endocrinology ◽

10.1210/en.2006-0041 ◽

2007 ◽

Vol 148 (5) ◽

pp. 2138-2147 ◽

Cited By ~ 41

Author(s):

Yun Ning ◽

Bao Hoang ◽

Alwin G. P. Schuller ◽

Tara P. Cominski ◽

Ming-Sing Hsu ◽

...

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Binding Protein ◽

Whole Body ◽

Normal Mammary Gland ◽

Igf Binding Proteins ◽

Essentially Normal ◽

Mammary Gland Involution ◽

Igf I ◽

Gland Development

IGFs (IGF-I and IGF-II) are essential for development, and their bioactivities are tightly regulated by six related IGF-binding proteins (IGFBPs). IGFBP-5 is the most highly conserved binding protein and is expressed in several key developmental lineages as well as in multiple adult tissues including the mammary gland. To explore IGFBP-5 actions in vivo, we produced IGFBP-5 knockout (KO) mice. Whole-body growth, selected organ weights, and body composition were essentially normal in IGFBP-5 KO mice, presumably because of substantial compensation by remaining IGFBP family members. The IGFBP-5 KO mice also exhibited normal mammary gland development and were capable of nursing their pups. We then directly evaluated the proposed role of IGFBP-5 in apoptosis and remodeling of mammary gland during involution. We found that the process of involution after forced weaning was delayed in IGFBP-5 KO mice, with both the appearance of apoptotic cells and the reappearance of adipocytes retarded in mutant mice, compared with controls. We also determined the effects of IGFBP-5 deletion on mammary gland development in pubertal females after ovariectomy and stimulation with estradiol/progesterone. In this paradigm, IGFBP-5 KO mammary glands exhibited enhanced alveolar bud formation consistent with enhanced IGF-I action. These results demonstrate that IGFBP-5, although not essential for normal growth, is required for normal mammary gland involution and can regulate mammary gland morphogenesis in response to hormone stimulation.

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