Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I

Richards, Randall G.; Klotz, Diane M.; Walker, Michael P.; DiAugustine, Richard P.

doi:10.1210/en.2003-1112

Cited by 84 publications

(74 citation statements)

References 20 publications

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“…Loss of IGF-I or IGF-IR expression in the mammary gland has been shown to result in a decrease in the number of TEBs, ductal branch points and ductal elongation (Ruan and Kleinberg, 1999;Bonnette and Hadsell, 2001;Richards et al, 2004). Delayed ductal growth and a reduction in TEB number was also observed in a transgenic mouse model overexpressing a constitutively activated IGF-IR in the mammary epithjleium (Carboni et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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Overexpression and hyperactivation of the type I insulinlike growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycyclineinducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.

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Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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“…pMEC were plated and incubated in basal media supplemented with insulin for 24 h. Cells were incubated under the same conditions in the absence or presence of TNFa, (10 ng/ml), IL-6 (100 ng/ml), IL-1b, (100 ng/ml), MCP-1 (100 ng/ml), PAI-1 (100 ng/ml), and IGF-I (10 ng/ml). Cells were incubated with hormone treatments for 4 days with a media change every 2 days, and [ prepubertal ductal growth is impaired in IGF-I null mice, but proceeds normally in mice retaining MFP IGF-I production even if deficient in plasma IGF-I (Ruan & Kleinberg 1999, Richards et al 2004. Current evidence suggests a similar role for the MFP in prepubertal cattle.…”

Section: Discussionmentioning

confidence: 99%

Regulation of mammary parenchymal growth by the fat pad in prepubertal dairy heifers: role of inflammation-related proteins

Thorn¹,

Purup²,

Vestergaard³

et al. 2007

Journal of Endocrinology

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In prepubertal heifers, the mammary parenchyma consists of epithelial and myoepithelial cells growing within a mammary fat pad (MFP). The MFP produces IGF-I that stimulates epithelial cell proliferation. In other species, adipose tissue expansion induces inflammation-related proteins (IRP), such as tumor necrosis factor a (TNFa), interleukin (IL)-6, IL-1b transforming growth factor b, monocyte chemoattractant protein 1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1). The MFP production of IRP may influence mammary development because they impair not only insulin but also IGF-I actions. Moreover, the MFP expansion seen with development and increased nutrition coincides with reduced parenchymal growth. Our first objective was to identify IRP capable of altering proliferation of bovine mammary epithelial cells. TNFa, but neither IL-6, IL-1b MCP-1 nor PAI-1, inhibited basal and IGF-I-stimulated proliferation in MAC-T cells and primary cells isolated from heifers. Our second objective was to determine whether MFP expression of IRP changed in a manner consistent with inhibition of parenchymal growth. MFP expression was measured from 100 to 350 kg body weight (experiment 1) or at 240 kg body weight (experiment 2) in dairy heifers offered restricted or high planes of nutrition. In experiment 1, neither nutrition nor development altered MFP expression of TNFa. Nutrition increased MCP-1 and PAI-1 but only before MFP expansion and after cessation of allometric parenchymal growth. In experiment 2, nutrition increased TNFa and PAI-1, but not MCP-1. Thus, MFP expansion increases IRP production in cattle, but this is unlikely to contribute to reduced parenchymal growth observed with development or increased nutrition.

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“…These tissues were fixed in 10% neutral-buffered formalin, sectioned and stained with H&E. For bromodeoxyuridine (BrdUrd) labeling of cells, mice were injected with BrdUrd (100 mg/kg) 2 hours before sacrifice. BrdUrd was detected by immunohistochemistry as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

Tumor Development by Transgenic Expression of a Constitutively Active Insulin-Like Growth Factor I Receptor

Carboni¹,

et al. 2005

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The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the

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Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I

Cited by 84 publications

References 20 publications

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Regulation of mammary parenchymal growth by the fat pad in prepubertal dairy heifers: role of inflammation-related proteins

Tumor Development by Transgenic Expression of a Constitutively Active Insulin-Like Growth Factor I Receptor

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